UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
**OFFICE OF CHEMICA** **L SA FETY**  **AN D**  **POLLUTION PREVENTION MEMORANDUM**  **Date :**  **9 /**  **10 /** **201 2**  **SUBJECT: Fluazinam**  . Human Health Risk Assessment to Support New Uses on Soy beans, the Melon Subgroup (9
- A), and the Pepper/Eggplant Subgroup (8
- 10 B) , and to Support Registration Review **PC Code: 129098 DP Barcode**  **s : D3**  **9 7**  **60 1**  **, D398687, D398690**  **Decision No s**  **.: 459601, 459565, 459568**  **Registration Nos. : 71512**  **- 1**  **, 71512 -**  **20 Petition No**  **s .:**  **1E7959, 2F7977, 8E7506 Regulatory Action: Section 3 Registration**  **and Registration Review**  **Risk Assessment Type: Single Chemical Aggregate**  **Case No.: 7013**  **T XR No.: NA**  **CAS No.: 79622**  **- 59**  **- 6**  **MRID No.: NA**  **40 CFR: §180.574 FROM:**  Douglas A. Dotson, Ph.D., Chemist

Karl yn Middleton, M.S., Toxicologist Zaida Figueroa , M.S., In dustrial Hygienist Registration Action Branch II Health Effects Division (7509P) **THROUGH:** Ed Scollon , Ph.D., Toxicologist

Dennis McNeill y , Chemist Margarita Collantes , M.S. , Biolog ist Christina Swartz, Branch Chief Registration Action Branch II Health Effects Division (7509P) **TO:** Andrew Ertman/Barbara Madden, RM Team 5, RIMUERB

Dominic Schuler/Tony

Kish, PM Team 22, Fungicide Branch Registration Division (7505P) and Steven Snyderman/Avivah Jakob, RMIB3 Pesticide Re
- evaluation Division (7508P)Fluazinam Human Health Risk Assessment DP No. D397601

Page 2 of 75 The Health Effects Division (HED) was requested to evaluate tolerance petitions associated with new uses proposed b y IS K Bio sciences (so yb eans) and the Inter regional Research Project No. 4 ( IR
- 4 , melons and peppers). The attached human health risk assessment addresses dietary , aggregate and oc cupational exposure and risk associated with the proposed uses of fluazinam, and there are no risks of concern. Additional toxicity

data required for fluazinam in conjunction with Registration Review have been submitted, evaluated and incorporated into th e current hazard characterization, endpoint and dose selection, and Food Quality Protection Act (FQPA) Safety Factor determination. All of the data HED required to support Registration Review have been submitted and the hazard and exposure databases are c omplete. In order to complete a preliminary risk assessment (PRA) for Registration Review, HED has incorporated the new information into the aggregate human health risk assessment for fluazinam. There are no dietary , residential or aggregate risks of concern assoc iated with the existing and proposed uses. Further, HED has reassessed occupational exposure and risk for the existing uses of fluazinam, using the most updated policies, surrogate data, transfer coefficients, and chemical
specific data submitted for fluazinam. In2009 HED concluded that because of the relatively low volume of incidents and the lack of moderate or severe health effects potentially related to fluazinam exposure, no further investigation was required to support the preliminary risk assessment. HED is not recommending any l abel changes or other mitigation for existing uses in conjunction with this risk assessment. Details regarding the risk assessment to support Registration Review are provided in Appendix F of the attached document.Fluazinam Human Health Risk Assessment DP No. D397601

Page 3 of 75 **1.0 Executive Summary** 
................................ ................................ ................................ .......... 5 **2.0 HED Recommendations** 
................................ ................................ ................................ . 10 **2.1 Data Deficiencies/Conditions of Registration** 
................................ ........................... 10 **2.2 Tolerance Considerations** 
................................ ................................ ........................... 10 **2.2 .1**  **Enforcement Analytical Method**
................................ ................................ ........... 10 **2.2 .2**  **International Harmoni zation** 
................................ ................................ ................. 11 **2.2 .3**  **Recommended Tolerances**
................................ ................................ ...................... 11 **2.2 .4**  **Re visions to Petitioned**  **- for Tolerances** 
................................ ................................ .. 11 **2.3 Label Recommendations** 
................................ ................................ ........................ 12 **3.0 Introduction** 
................................ ................................ ................................ ..................... 12 **3.1 Chemical Identity** 
................................ ................................ ................................ ........ 12 **3.2 Physical/Chemical Characteristics** 
................................ ................................ ............ 12 **3.3 Pesticide Use Pattern**  **for Proposed Commodities**
................................ .................... 12 **3.4 Anticipated Exposure Pathways** 
................................ ................................ ................ 14 **3.5 Consideration of Environmental Justice** 
................................ ................................ .. 14 **4.0 Hazard Characterization and Dose**  **- Response**  **Characterization**
............................... 14 **4.1 Toxicology Studies Available for Analysis** 
................................ ................................ 1 5 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)** 
............................ 1 5 **4.2.1 Dermal Absorption** 
................................ ................................ ................................ . 1 5 **4.3 Toxicological Effects** 
................................ ................................ ................................ ... 1 6 **4.4 Safety**  **F actor for Infants and Children (FQPA Safety Factor)** 
.............................. 1 8 **4.4.1 Completeness of the Toxicology Database** 
................................ ............................ 1 8 **4.4.2 Evidence of Neurotoxicity** 
................................ ................................ ...................... 1 8 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal** 
...... 1 9 **4.4.4 Residual Uncertainty in the Exposure Database** 
................................ .................. 1 9 **4.5 Toxicity Endpoint and Point of Departure Selections** 
................................ ............. 20 **4.5.1 Dose Response**  **Assessment**
................................ ................................ ..................... 20 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment** 
... 2 1 **4.5.3 Classification**  **of Carcinogenic Potential**
................................ ............................... 2 1 **4.5.4 Summary of Toxic**  **ological Doses and Endpoints for Fluazinam**
....................... 22 **5.0 Dietary Exposure and Risk Assessment** 
................................ ................................ ........ 24 **5.1 Metabolite/Degradate Residue Profile** 
................................ ................................ ...... 24 **5.1.1 Summary of Plant and Animal Metabolism Studies** 
................................ ........... 24 **5.1.2 Summary of Environmental Degradation** 
................................ ............................ 25 **5.1.3 Comparison of Metabolic Pathways** 
................................ ................................ ...... 25 **5.1.4 Residues of Concern Summary and Rationale** 
................................ ..................... 26 **5.2 Food Residue Profile** 
................................ ................................ ................................ ... 27 **5.3 Water Residue Profile** 
................................ ................................ ................................ . 28 **5.4 Di**  **etary Risk Assessment**
................................ ................................ ............................ 2 9 **5.4.1 Description of Residue Data Used in Dietary Assessment** 
................................ .. 29 **5.4.2 Percen**  **t Crop Treated Used in Dietary Assessment**
................................ ............. 30 **5.4.3 Acute Dietary Risk Assessment** 
................................ ................................ ............. 30 **5.4.4 Chronic Dietary Risk Assessment** 
................................ ................................ ......... 30 **5.4.5 Cancer Dietary Risk Assessment** 
................................ ................................ ........... 30 **5.4.6 Summary Table** 
................................ ................................ ................................ ....... 30Fluazinam Human Health Risk Assessment DP No. D397601

Page 4 of 75 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization** 
............................ 31 **6.1 Residential Handler Exposure**  **and Risk**
................................ ................................ ... 31 **6.2 Residential**  **Post -**  **a pplication Exposure** 
................................ ................................ ..... 31 **6 .2.1**  **Dermal Post**  **- application**  **Exposure**
................................ ................................ ........ 31 **6 .2.**  **2 Inhalation**  **Post -**  **application Exposure** 
................................ ................................ ... 32 **6.3 Combined**  **Residential Risk Estimates**
................................ ................................ ...... 32 **6. 4**  **Residential Risk Estimates for Use in Aggregate Assessment**
................................ 32 **6.5 Spray Drift** 
................................ ................................ ................................ ................... 32 **6.6 Residential Bystander Post Application Inhalation Exposure** 
................................ 3 3 **7.0 Aggregate**  **Exposure/Risk Characterization**
................................ ................................ . 33 **7.1 Acute Aggregate Risk** 
................................ ................................ ................................ . 34 **7.2 Short**  **- /** **Intermediate -**  **Term Aggregate Risk Estimates** 
................................ ............ 34 **7.3 Chronic**  **Aggregate Risk**
................................ ................................ ............................. 35 **7.4 C**  **an c**  **er Aggregate Risk** 
................................ ................................ ............................... 35 **8.0 Cumulative Exposure/Risk Characterization** 
................................ .............................. 35 **9.0 Occupational Exposure/Risk Characterization** 
................................ ........................... 35 **9.1 Occupational**  **Handler Exposure/** **Risk Estimates** 
................................ ..................... 35 **9.2 Occupational**  **Post -**  **a pplication**  **Exposure/ Risk**  **Estimates**
................................ ....... 3 7 **9.2.1 Occupational**  **Post -**  **application Inhalation**  **Exposure /Risk Estimates** 
................ 3 9 **9.2.2 Occupational**  **Post -**  **application Dermal**  **Exposure /Risk Estimates** 
..................... 3 9 **10.0 References** 
................................ ................................ ................................ ........................ 41 **Appendix A. Flu**  **a zinam**  **Toxicology Profile**  **and Additional Information**
............................ 4 3 **A.1 Toxicology**  **Profile Tables for Fluazinam** 
................................ ................................ .. 4 3 **A.2 Triple Pack Analysis for Fluazinam** 
................................ ................................ .......... 50 **A.3 HEC Inhalation Calculations** 
................................ ................................ ..................... 52 **A. 4**  **Hazard Identification and Endpoint Selection**
................................ ......................... 55 **Appendix B**  **. International Residue Limit Status Sheet** 
................................ ......................... 60 **Appendix C**  **. Fluazinam**  **Physical/Chemical Properties**
................................ ......................... 62 **Appendix D**  **. Review of Human Research**
................................ ................................ ................ 63 **Appendix E**  **. Structures of Fluazinam Metabolites and Degradates of Concern** 
................. 64 **Appendix F**  **. Occupational Exposure and Risk Assessment for**  **R egistered Uses** 
................ 66Fluazinam Human Health Risk Assessment DP No. D397601

Page 5 of 75 **1.0 Executive Summary**  ISK Biosciences and the Interregional Research Project No. 4 (IR
- 4) submitted petitions to establish tolerances for the fungicide fluazinam in/on soy beans and the commodities of the melon and pepper/eggplant subgroups (9
- A and 8
- 10B, respectivel y). This human health risk assessment presents HED’s conclusions with respect to the risk estimates associated with the proposed uses as well as all registered uses for fluazinam. The toxicity and exposure databases for fluazinam are complete in accordance with the requirements of registration review , and therefore this document also serves as HED’s human health risk assessment to support registration review
. The proposed u ses on melons and peppers were evaluated under a joint review with Canada’s Pesticide Management Regulatory Agency (PMRA). F luazinam ( 3
- chloro
-N

- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl )
- 2
- py ridinamine ) i s a preventive contact f ungicide with a multi
- site fungicidal mode of action. It disrupts the production of energy at several metabolic sites within the fungal cell. Fluazinam is a protectant fungicide . When it is applied to plants, it remains primarily on the plant surface an d kills any fungal spores that come into contact with it . It is not taken up to any extent by the plant and , unlike sy stemic fungicides, is not translocated within the plant. HED has assessed exposures and risks from the registered and proposed uses of fluazinam. The end
- use product proposed for use on melons, peppers, and so ybeans is OMEGA ® 500F (EPA Reg. No. 71512
- 1), a soluble
- concentrate (SC) formulation containing 40% ai fluazinam (4.17 lb s ai/gal). OMEGA ® 500F may be applied as a foliar spray usi ng aerial, ground , and handheld equipment. Itmay

also be applied via chemigation. The maximum single application rates for the proposed uses range from 0.52
- 0.78 lb ai/A. For melons and peppers, the label allows up to 6 applications at 0.78 lb ai/A for a total seasonal application rate of 4.68 lb ai/A. The proposed PHIfor these commodities is 30 day s. For soy beans, the label allows up to 2 applications at 0.52 lb ai/A for a total seasonal application rate of 1.04 lb ai/A. Occupational e xposure from use on soy beans, melons, and peppers is expected to be of short
- to intermediate
- term duration s . Hazard Characterization and Endpoint Selection The 28
- day

inhalation and immunotoxicity studies required during registration review were submitted and evalu ated, and the toxicology datab ase for fluazinam is complete
. The liver is a primary

target organ following dosing with fluazinam . Numerous liver effects were observed in rats, mice, and dogs. Liver effects were also observed in rats following dosing via the dermal route. Treatment
- related effects were also noted in other organs; however, these effects were not regularly observed in all three species or in all studies in a given species. No signs of neurotoxicity were observed in an acute neurotoxicity study or in two subchronic neurotoxicity

studies. However, a neurotoxic lesion described as vacuolization of the white matter of the central nervous sy stem (CNS) was observed in subchronic and chronic studies in mice and dogs, as well as in special studies in rats. After further investigation, it was determined that an impurity was responsible for the appearance of the white matter vacuol iz ation. A developmental neurotoxicity (DNT) study

c ontaining a lower concentration of the impurity wasFluazinam Human Health Risk Assessment DP No. D397601

Page 6 of 75 submitted to address the Agency ’s concerns regarding the vacuolization ; i n the study , there was no evidence of vacuol iz ation of the brain or any other treatment
- related pathology up to the highest dose te sted. Because of the lower concentration of the impurity in the technical used in the DNT, and because of the absence of the lesion in the study , HED concluded that fluazinam, per se , was not responsible for the induction of th e lesion. Furthermore, HED is not concerned about the presence of the impurity, since the acute and chronic reference doses selected for risk assessment are protective of any possible neurotoxic effects resulting from exposure to the impurity
. In an immunotoxicity

study in mice, significant suppressions of anti sheep red blood cell (anti
SRBC ) antibody
- forming cell assay (AFC) response were demonstrated at the highest dose tested indicating potential immunotoxicity . However, clear NOAELs and LOAELs were identified for the effects seen in the study and the points of departure (PODs) and endpoints selected for risk assessment are protective of immunotoxic effects. In a subchronic inhalation toxicity study in rats, pulmonary

effects were observed at the mid and high doses. These effects included dose related increases in lung/bronchial weights and increased incidences of alveolar macrophages and peribronchiolar proliferation in both sexes. There was no evidence of increased quantitative or qualitative susceptibility in a develop mental toxicity study in rabbits or in a 2
- generation reproduction study in rats. In a developmental toxicity study in rats, there was no evidence of increased quantitative susceptibility ; however, there was evidence of increased qualitative susceptibility. Developmental effects were seen in the presence of minimal maternal toxicity
. The registrant submitted a developmental neurotoxicity

study (DNT) in rats . There was evidence of increased quantitative susceptibility in the DNT study , i.e., offspring ef fects were seen in the absence of maternal toxicity . The registrant also submitted a series of special studies in order to address the issues of increased susceptibility

and the presence of neurotoxic lesions observed in the toxicological database. The concern is low for the increased susceptibility seen in the developmental toxicity and DNT studies because clear NOAEL s were established, dose
- responses were well defined, and the most sensitive endpoints were used for risk assessment , in order to be p rotective of the observed susceptibility
. The required 10x FQPA Safety Factor was reduced to 1x b ased on 1) the completeness of the toxicology database ; 2) the lack of neurotoxicity ; 3) the lack of residual uncertainty for pre
- and post natal toxicity ; an d 4) because the exposure assessment is conservative and does not underestimate exposure **.** HED’s Cancer Assessment Review Committee (CARC) classified fluazinam as having “Suggestive evidence of carcinogenicity , but not sufficient to assess human carcinogenic potential.” The CARC also determined that the quantification of cancer risk using a non
- linear approach (i.e., RfD) would adequatel y account for all chronic toxicity, including carcinogenicity , that could result from exposure to fluazinam. The dose and endpoint for acute dietary risk assessment (general population) w ere selected from an acute neurotoxicity

study in which clinical signs including decreased motor activity and soft stools observed were observed at high doses. For acute dietary risk assessment for females 13
- 49, a developmental toxicity study in rabbits was used , and the endpoint selected was total litterFluazinam Human Health Risk Assessment DP No. D397601

Page 7 of 75 resorptions and skeletal abnormalities. For the chronic dietary risk assessment, the carcinogenicity

study in mice and the chronic study in dogs were selected as co
- critical studies. In the mouse, effects seen were mainl y in the liver. In dogs, nasal dryness and gastric l ymphoid hy perplasia were observed. Route
- specific toxicity

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

or assessing short - and intermediate
- term dermal exposure. For the inhalation route, HED selected the endpoint from the subchronic inhalation toxicity study based on portal
- of

- entry effects (pulmonary) . In accordance with current guidance, human equivalent concentrations (HECs) and human equivalent doses (HEDs) were calculated , with the HEDs being used for risk assessment. The dermal and inhalation studies are prote ctive of the developmental effects seen in rats as well as potential neurotoxicity and immunotoxicity
. The short
- /intermediate
- term toxicological endpoints for fluazinam are the same for the respective routes of exposure . As a result, only short
- term dermal and inhalation exposures were assessed for occupational and residential scenarios . The resulting short
- term risk estimates are considered to be protective of intermediate
- term exposure and risk. For acute and chronic dietary and dermal risk assess ments, a 100 x uncertainty factor was applied ( 10 x interspecies factor and 10x intraspecies factor). The 100x factor w as used to calculate the acute and chronic reference doses (RfDs) , which are the same as the respective population adjusted doses (PADs)
. For the dermal assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined uncertainty factors. For inhalation risk assessments, the LOC is an MOE of 30 based on an interspecies factor of 3 x and an intraspecies fact or of 10 x ; the interspecies factor was reduced from 10x to 3x, since calculation of human equivalent calculations (HECs) accounts for pharmacokinetic (not pharmacody namic) interspecies differences between animals and humans. Metabolism/Metabolites and Degradates of Concern The metabolism of fluazinam in primary crops, rotational crops, and animals has been adequatel y delineated. The residue of concern for risk assessment in bulb vegetables as well as in root and tuber vegetables is parent fluazinam. For all other plant commodities, the residues of concern in plants for risk assessment are fluazinam and its metabolite AMGT. In drinking water, the degradates of concern for risk assessment are parent fluazinam and its transformation products. In livestock commodities, the residues of concern for risk assessment are fluazinam, the metabolites known as AMPA, DAPA, and their sulfamate conjugates. Food Residue Profile The food use profiles for the registered and proposed commodities are complete and adequate for tolerance setting and risk assessment purposes , including registration revi ew . For so ybeans, melons, and peppers, the registrants submitted adequate field trial and processing data for parentFluazinam Human Health Risk Assessment DP No. D397601

Page 8 of 75 and the metabolite AMGT. For all crops, adequate numbers of trials were performed in the recommended NAFTA growing zones. The OECD MRLcalcul ation procedures were used for determining appropriate tolerance levels. The recommended tolerances for soy bean seed, soy bean hulls, the melon subgroup, and the pepper/eggplant subgroup are listed in Table 2.2.3. A dequate anal ytical methods are available for enforcement of tolerances in plant and livestock commodities. In addition, the FDA Multiresidue Methods ( M RM s ) can serve as a confirmatory procedure for residues of fluazinam , but not for the metabolites
. The necessary anal ytical reference standards for fluazinam are available in the EPA National Pesticide Standards Repository
. Dietary Exposure and Risk Acute and chronic dietary exposure and risk assessments were conducted , including food and drinking water contributions from the existing uses as w ell as the proposed uses
. The acute and chronic assessments are based on 100% crop treated assumptions and incorporate modeled estimated drinking water concentrations (EDWCs) that account for both parent fluazinam and its transformation products. D efault processing factors were used for all processed commodities for which default factors were available
. The acute analy sis is based on tolerance
- level residues for all commodities and uses high
- end residue estimates for the metabolite AMGT. The chronic analysis is based on tolerance
- level residues for all commodities except apples. For apples, the average field trial value was used. As a result, the acute and chronic exposure and risk estimates are considered to be conservative. The acute and chronic die tary risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children. The acute dietary

risk estimate for the general U.S. population is 5.3 % of the acute PAD (aPAD). The population subgroup with the highest acute dietary risk estimate is Females 13
- 49, which uses 2 8 % of the aPAD. The chronic dietary risk estimate for the general U.S. population is 20 % of the chronic PAD (cPAD). The most hi ghl y exposed population subgroup is All Infants (<1 ye ar old), which uses 51 % of the cPAD. As the c hronic dietary endpoint and dose are protective of potential cancer effects, cancer dietary risk is also not of concern. Because such conservative assumpti ons were made in the assessments, HED is confident that the acute and chronic dietary exposure assessments do not underestimate risk to the general U.S. population or any population subgroup or life stage . Residential Exposure and Risk The residential e xposure database is complete and adequate
. There are no proposed residential uses; however, there is an existing use of fluazinam on golf course turf. Individuals can be exposed when they

play golf on treated turf, and therefore a residential dermal post
- application assessment was previously conducted for golfers. Residential post
- application exposure to golfers was assessed using the HED Standard Operating Procedures (SOPs) for Residential Exposure Assessment (2012), as well as chemical
- specific residue data from the turf transferable residue (TTR) study. Dermal post
- application exposure and risk estimates for golfers resulted in MOEs greater than the LOC of 100 , and were not of concern (e.g., lowest MOE = 780)
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 9 of 75 Aggregate Exposure and Risk The acute and chronic aggregate risk estimate s are equivalent to the corresponding dietary (food plus water) risk estimate s, which are not of concern. Chronic dietary exposure is considered to be a background exposure level to which the s hort
- term residential exposure is added. The short
term aggregate risk assessment s resulted in estimated MOEs of 7 30 to 97 0. For fluazinam, the LOC for short
- term risk is an MOE of 100. As the resulting aggregate MOEs exceed the LOC of 100, aggregate dietary

and residential risk estimates are not of concern. Occupational The occupational exposure database is complete and adequate for assessing occupational exposure to fluazinam for both the registered and proposed uses. It is HED policy

to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical
- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. Default assumptions established by HED’s Science Advisory Council for Exposure were used for parameters such as body weight, acres treated , and amount handled. Occupational handler assessments considered both dermal and inhalation short
- term exposures. The estimates are considered to be protective of intermediate
- term exposure and risk. For the proposed uses on so ybeans, melons , and peppers, all the occupational handler scenarios resulted in MOEs equal to or greater than the respective levels of concern at some level of personal protecti ve equipment ( PPE , e.g., baseline ( single layer clothing, no respirator) , chemical
- resistant gloves, double layer clothing), and assuming engineering controls (i.e., en closed cockpit) for aerial applications
. Based on the dermal and inhalation risk estimates, no additional PPE or other mitigation is need ed on the label , either for the existing or proposed uses
. Based on the Agency ’ s current practices, a quantitative non
- cancer occupational post
- application inhalation exposure assessment i s not being performed for fluazinam at this time
. Although a quantitative occupational p ost - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers (e.g., flaggers)
. H andler inhalation exposure estimates are considered to be protective of occupational post
applic ation inhalation exposure scenarios. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post
- application inhalation exposure assessment for fluazinam. There is potential for dermal exposure during occupational post - application activities , such as crop maintenance activities, scouting, irrigation, and harvesting . Chemical
- specific dislodgeable foliar residue (DFR) studies were submitted b y the registrant and reviewed by HED , and the results of these studies were incorporated into HED’s review of the existing and proposed uses
. Post
- application dermal exposure and risk estimates for the proposed uses resulted in MOEs greater than the LOC of 100 and are not of concern on Day 0 (i.e., 1 2 hours after application).Fluazinam Human Health Risk Assessment DP No. D397601

Page 10 of 75 Restricted Entry

Interval (REI) The restricted entry

interval (REI) for fluazinam is based on the acute toxicity of the technical material. Fluazinam is classified as Toxicity Category Ifor eye irritation. Under the Worker P rotection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute Toxicity Category Ifor any route is assigned a 48
- hour REI
. Based on the acute toxicity profile of fluazinam, the 48
- hour REIspecified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post
- application exposures to fluazinam on melons, peppers , and soy beans. **2.0 HED**  **Recommendations** HED recommend s in favor of granting the proposed Section 3 use of fluazinam on soy beans, the Melon subgroup (9
- A), and the Pepper/Eggplant subgroup (8
- 10 B)
. **2.1 Data Deficiencies/Conditions of Registration**  None **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  An adequate GC/ECD method (6148
- 94
- 0170
- MD
- 001) is available for enforcing fluazinam tolerances on plant commodities. The method was adequately radiovalidated and underwent a successful ILV trial. The method was forwarded to BEAD’s Anal ytical Chemistry Branch (ACB) for a TMV trial, and was subsequentl y determined to be suitable as a tolerance
enforcement method. The method LOQ is 0.01 ppm for fluazinam in plant commodities. An adequate enforcement method for determination of AMGT is also available. The method is an HPL C/UV method entitled “Method Evaluation for the Anal ys is o f AMGT in Grapes.” The registrant submitted an adequate ILV for the method. The range of fortification levels and the percent recovery

values were acceptable. ISK Biosciences Corporation’s analy tical method entitled “ Enforcement Method for the Analy sis of Fluazinam and its Metabolites AMPA and DAPA in Milk and Meat” is adequate as an enforcement method for residues of fluazinam, AMPA, and DAPA and their sulfamate conjugates in kidney , liver, and fat. The method was successfully validated for f

luazinam, AMPA, and DAPA in beef kidney , beef liver , and beef fat. Adequate FDA multiresidue method ( MRM) testing data are available for fluazinam and its metabolite AMGT. As fluazinam is partially recovered through Sections 302, 303, and 304 of PAM Volume I , the M RM s can serve as a confirmatory procedure for residues of fluazinam. The FDA MRM methods are not suitable for determining residues of AMGT.Fluazinam Human Health Risk Assessment DP No. D397601

Page 11 of 75 **2.2.2 International Harmonization**  There are no harmonization issues between the U.S., Cod ex, Canada, and Mexico. There are currentl y no Codex MRLs for fluazinam on any commodities including melons, bell peppers, non - bell peppers, or so yb eans. There are no Canadian or Mexican MRL s for melons or peppers. The petition for melons and peppers is being evaluated jointly by the EPA and PMRA , and the MRL s for melons and peppers will be harmonized between the two countries. There are no harmonization issues between the U.S. and Canada with respect to soy bean commodities. There is a Canadian MRLof 0.10 ppm for edible
- podded soy bean. There is no need to harmonize this MRLwith HED’s recommended tolerance of 0.01 ppm for soy bean seed because edible
- podded soy bean and so ybean seed are different commodities. Edible
- podded so yb ean is an immature seed that includes the pod. It is likel y to have a higher residue level than soybean seed, which is the dried seed alone. The U.S. and Canadian MRL s are harmonized for all other commodities for which both countries have established MRLs (potatoes (0.02 ppm), b ushberries (7.0 ppm) , Brassica leafy vegetables (0.01 ppm), dried shelled peas and beans (Subgroup 6C, except pea, 0.02 ppm) , and edible podded peas and beans (Subgroup 6A, except pea, 0.10 ppm)
. Mexico adopts U.S. tolerances and/or Codex MRL s for its export purposes. For the purpose of registration review, no additional tolerance changes are needed to achieve harmonization. **2.2.3 Recommended Tolerances**  The recommended tolerances are listed in Table 2.2.3 , and should be added to the table in 40CFR §180.574(a)(1): Tolerances are established for residues of f luazinam, 3
- chloro
-N

- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl)
- 2
- py ridinamine ), including its metabolites and de gradates, in or on the commodities in the table. Compliance with the tolerance levels is to be determined b y measuring only fluazinam. **Table 2.2.3**  **. Tolerance Summary for F**  **luazinam** Commodity as Proposed by Registrant Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Melon subgroup 9A 0.08 0.07 Pepper/eggplant subgroup 8
- 10B 0.10 0.09 Soy bean, Seed 0.01 0.01 Soy bean, seed Soy bean, Hulls 0.02 0.05 Soy bean, hulls **2.2.4 Revisions to Petitioned**  **- For**  **Tolerances** The proposed tolerances for so ybean hulls, melons, and peppers are different from the tolerances recommended b y HED. The reason for the differences is that the registrant determined the proposed tolerances using the NAFTA tolerance calculator , while Canada and the U.S. agreed to use the OECD calculation procedures for melons and peppers
. The U.S. is also using the OECDFluazinam Human Health Risk Assessment DP No. D397601

Page 12 of 75 calculation procedures for soy bean commodities. Revised Section s F should be submitted by IR
4 and the registrant, to reflec t HED’s tolerance recommend ations
. No changes are needed to the tolerance expressions. **2.3 Label Recommendations**  None **3.0 In**  **troduction 3.1**  **Chemical Identity T**  **able 3.1.**  **Fluazinam Nomenclature**  Com pound Chemical Structure

Em pirical Formula C 13 H 4 Cl 2 F 6N 4 O 4 Molecular Weight 465.1 Common Name Fluazinam Com pany Experimental Names Fluazinam, IKF
- 1216 IUPAC Name 3
- chloro
-N
- (3
- chloro
- 5
- trifluoromethyl
- 2
-py ridyl)
- α,α,α - trifluoro
- 2,6
- dinitro
p - toluidine CAS Name 3
- chloro
-N
- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl)
- 2
-py

ridinamine CAS Number 79622
- 59
- 6 End
- use Product/(EP) Omega ® 500F Fungicide (EPA Reg. No. 71512
- 1) Fluazinam Turf Fungicide (EPA Reg. No. 71512
- 20) **3.2 Physical/Chemical Characteristics**  Fluazinam has a relatively high octanol/water partition coefficient. The l og KOW value is 3.56 ( KOW = 3 , 63 0 ). F luazinam has a vapor pressure of 1.7 3 x 10 - 7 mm Hg at 2 5 oC
. See Appendix C for a listing of fluazinam ’s p hy sical and c hemical properties. **3.3 Pesticide Use Pattern**  **for Proposed Commodities** There is currentl y a single end
- use product (EP) for fluazinam registered in the U.S. for use on several food and feed crops. This product is Omega ® 500F (EPA Reg. No. 71512
- 1), which is a N N H C F 3 Cl

Cl C F 3 N O 2 O 2NFluazinam Human Health Risk Assessment DP No. D397601

Page 13 of 75 4.17 lb/gal soluble
- concentrate (SC) formulation
. ISK Biosciences and IR
- 4 are proposing to add uses on so ybeans, the melon subgroup (9A) , and the pepper/eggplant subgroup (8
- 10B) to the registered label . The prop osed use directions are summarized in Table 3.3
. OMEGA ® 500F may

be applied as a foliar spray using aerial, chemigation (i.e., sprinkler irrigation sy stem), ground and handheld equipment . The proposed Restricted Entry Interval (REI) is 48 hours for all c rops. The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, flaggers , and other handlers to wear long
- sleeved shirt and long pants, socks, chemical
- resistant gloves and footwear, and protective eyewear. When mixing and loading also wear a chemical
- resistant apron. Mixers/L oaders must wear a dust/mist filtering respirator (MSHA/NIOSH TC
- 21C) or a NIOSH approved respirator with an N, R, P or HE filter.
**Table 3.3**  **. Summ ary of Directions for**  **Proposed Use of**  **Fluazinam on Melons, Peppers and Soybean**  **s Applic. Timing,**  **Type, and Equip. Form** **ulation**

**[ EPA Reg.**  **No. 71512 -**  **1 ]**  **Max. Single**

**Applic ation**  **Rate (lb ai/A)**  **† Max. No.**  **of**

**Applic ations**  **per Season Max. Seasonal** 

**Applic ation**  **Rate (lb ai/A) PHI** 

**(days) Use Directions and** 

**Limita tions**  **Melons (Crop Sub g**  **roup 9A)** Broadcast ; Ground, Chemigation (Sprinkler System). OMEGA® 500F

40% ai, Soluble Concentrate (4.17 lb ai/gal) 0.78 lb ai/A

(24 fl oz/A) 6 4.68 lb ai/A ( 144 fl oz/A) 30 Re
- treatment Interval = 7
- 10 days
. Apply when disease symptoms first appear. **Peppers (Crop Sub g**  **roup 8 -**  **10B)** Broadcast; Ground, Chemigation (Sprinkler System), Soil Drench (at transplanting). OMEGA® 500F 40% ai, Soluble Concentrate (4.17 lb ai/gal) 0.78 lb ai/A

(24 fl oz/A) (0.013 lb ai/gal) 6 4.68 lb ai/A ( 144 fl oz/A) 30 Re
- treatment Interval = 7
- 14 days
. Apply as a soil drench at transplanting. Foliar applications should begin 7 days after transplanting. **Soybean** Apply at early bloom to full bloom stage of development. Broadcast; Aerial, Ground. OMEGA® 500F

40% ai, Soluble Concentrate (4.17 lb ai/gal) 0.52 lb ai/A

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

Stage R33 Re
- treatment Interval = 10
- 14 days (at early pod formation). For preventive treatment or low disease pressure use low rate. Do not feed hay from treated field to livestock or allow livestock to graze on treated areas. Do not apply after early pod formation. **†** Maximum Single Application Rate for Soybeans (lb ai/A) = (1 pint/A)(16 fl oz/1 pint) (4.17 lb ai/gal)(1 gal/128 fl oz) = 0.52 lb ai/A. Maximum Single Application Rate for Melons & Peppers (lb ai/A) = (24 fl oz/A) (4.17 lb ai/gal)(1 gal/128 fl oz) = 0.78 lb ai/A. Maximum Single Application Rate for Peppers (lb ai/gal) = ( 0 .78 lb ai/A)/(60 gal/A) = 0.0 13 lb ai/gal. The proposed (and current) product label for the 4.17 lb/gal soluble
- concentrate (SC) formulation specifies that a pplications are allowed through the following types of irrigation sy stems: center pivot, motorized lateral move, traveling gun, solid set , or portable (wheel move, side roll, end tow, or hand move). The label contains the following rotational crop restriction s :Fluazinam Human Health Risk Assessment DP No. D397601

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

volumes are 20
- 100 gal/A (20
- 60 gal A for field/row crops) for dilute spray applications and 5
- 10 gal/A for ground and aerial spray applications. As the proposed supplemental label states that chemigation (i.e., sprinkler irrigation) will be permitted on melons and peppers, chemigation was assessed for the proposed uses. **3.4 Anticipated Exposure Pathways**  Humans m ight be exposed to fluazinam i n food and drinking water because fluazinam may be applied directl y to row crops and golf course turfgrass
. The onl y residential exposure scenario expected for fluazinam is dermal post
- application exposure to treated golf course turf. The registered and proposed use s also result in the potential for occupational (handler/p ost application) exposures. In addition, applicators might be exposed while handling the pesticide prior to application, mixing/loading the pesticide, and during application. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and L o w - Income Populations, ” (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf )
. As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) , and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups , and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non
- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths , and adults entering or playing on treated areas post
- application are evaluated. Further considerations are currently in development , as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard**  **Characterization and Dose**  **- Response Characterization**  Fluazinam is a preventive contact fungicide with a multi
- site mode of action. The fungicidal mode of action involves disruption of the production of energy at several metabolic sites within the fungal cell. Fluazinam is a protectant fungicide . Un like s ystemic fungicides , i t is not takenFluazinam Human Health Risk Assessment DP No. D397601

Page 15 of 75 up to any extent by the plant, and is not translocated within the plant. When applied to plants it remains primaril y on the plant surface. The mammalian mode of action is unknown at this time. **4.1 Toxicology Studies Av**  **ailable for Analysis** The toxicology

database for fluazinam is complete . The available studies include: subchronic oral toxicity

studies in rats, mice, and dogs ; a chronic oral toxicity study in dogs ; carcinogenicity studies in rats and mice ; developmental and reproduction studies in rats and a developmental study in rabbits ; subchronic dermal and inhalation toxicity studies in rats ; and an immunotoxicity study in mice . There is also a metabolism study in the rat , a complete mutagenicity battery , and acut e LD50 and neurotoxicity studies (acute, subchronic, and developmental). **4.2 Absorption, Distribution, Metabolism, Excretion (ADME)**  In the rat metabolism study , o verall recovery of the administered radioactivity was acceptable (93.10
- 103.55%). Excretion via the urine was minor. AMPA mercapturate and DAPA, the major urinary

metabolites, represented onl y 0.05
- 0.39% of the administered dose. Radioactivity in the fe ces represented most of the administered dose (88.78
- 100.0%). Identified fecal metabolites, however, represented from 11.20
- 68.59% of the administered dose. For all dose groups, most of the fecal radioactivity appeared to reside with unextractable compon ents in the post - extraction solids (PES). Further anal ys is of the PES components using base hydrol ys is indicated that most of this radioactivity could be attributed to hydrol ys is products of AMPA and DAPA. PES radioactivity was also greatest for the low
- dose group , which was consistent with the lower overall accounting of identified metabolites for this group. Approximately 20
- 25% of the aqueous phase of the fecal extraction was identified as a cy steine conjugate of DAPA and represented <1% of the admini stered dose. With the exception of the low
- dose group, parent compound represented most of the identified radioactivity in the feces. AMPA and DAPA were identified in the feces from all dose groups , but these metabolites never represented more than 5% of the administered dose (except for high
- dose female rats where AMPA accounted for 10.22%). DAPA glucuronide and AMPA mercapturate were the major biliary metabolites , but represented <4% of the administered dose. Total biliary radioactivity , however rep resented 25
- 34% of the administered dose
. Analy sis of chromato grams indicated that numerous other metabolites were present in the bile , but were individually of insufficient quantity

to allow for characterization. Metabolite profiles from administrati on of different label positions (py ridyl and phenyl ) indicated that there was no metabolic cleavage of the ring structures. Minor quantitative differences in metabolite recovery were observed between genders , but not of sufficient magnitude to suggest bio logicall y relevant differences in the metabolism of fluazinam
. **4.2.1 Dermal Absorption**  An in vivo d ermal absorption study in rats is available for fluazinam that demonstrates low dermal absorption of 4%. Additionally , in vitro dermal data are available in rat and human skin, along with a dermal toxicity study in rats . In the rat study , liver effects were seen at the lowestFluazinam Human Health Risk Assessment DP No. D397601

Page 16 of 75 observed adverse effects level (LOAEL) of 100 mg/kg/day , with a no observed adverse effects level (NOAE L ) of 10 mg/kg/day . In an e ffort to refine the dermal point of departure selected for risk assessment, the dermal absorption data and dermal toxicity study were used to calculate a refined human dermal equivalent dose that was used for short
- and intermediate
- term dermal risk assess ments. To calculate a RDD, in vitro results using rat skin are corrected for any differences between in vitro and in vivo absorption rates and species differences between rats and humans. This refinement in dermal absorption is important because absorpti on by human skin is usually lower than that b y rat skin. Accordingl y, the combined use of the data from the three studies and two testing s ys tems offers greater precision in estimating human dermal absorption, which strengthens the reliability of the derm al risk assessment ( see Appendix A.2). **4.3 Toxicological Effects**  In subchronic and chronic oral and dermal studies in rats, dogs , and mice, the liver was a primary target organ. In rats, subchronic exposure resulted in increased liver weights and liver histopathology

(hepatocyte hy

pertrophy , sinusoidal chronic inflammation , and necrosis). In dogs, increased liver enzy mes (alkaline phosphatase), increased liver weights, and histop athology

(hepatic coagulative necrosis, and bile duct hy perplasia) were observed. In mice, increased liver weights, and liver hy pertrophy were seen. Liver histopathology (h yp ertroph y, necrosis, brown pigment, and apoptosis) was also noted in maternal ani mals in a preliminary developmental toxicity

study in rabbits. Chronic exposure in rats led to similar liver effects, along with gross lesions (pale, enlarged, pitted, and mottled livers , and accentuated markings on the liver) and more pronounced liver hi stopathology ( eosinophilic or basophilic hepatocy tes, rarefied or vacuolated hepatocy tes, altered foci, single cell necrosis, hy pertrophy , and fatty change ). In dogs, liver effects were limited to increased alkaline phosphatase and liver weights after lon g - term exposure. In mice, basophilic and/or eosinophilic vacuolated hepatocy tes, hepatitis, and brown pigmented macrophages were observed after chronic exposure, with the addition of hepatocellular adenomas/carcinomas at the HDT
. Tre atment - re lated effects were also observed in other organs in subchronic and chronic oral, dermal , and inhalation studies in rats, dogs , and mice, but these effects were not regularl y noted in all three species or in all studies in a given species. In rats, effects obser ved were decreased body weight gain, decreased food consumption, mild anemia, and clinical chemistry alterations ( increased serum cholesterol, phospholipid, and aspartate aminotransferase ). T esticular atrophy and increased testicular weights (inhalation s tudy), pancreatic exocrine atrophy , increased lung weights and increased alveolar adenomatosis, epithelialization , and macrophages were also observed. Additionall y , thy roid gland follicular cell hy perplasia and an increased incidence of thy roid gland foll icular cell tumors in male rats, but not in female rats , were seen . In dogs, effects included increased salivation and increased nasal dry ness, grey mottling of the retina, mild anemia, and gastric ly mphoid hy

perplasia. In mice, increased mortality (at h igh doses), decreased body weight gain, increased serum glucose, increased kidney weights, cystic thyroid follicles, and an increased incidence of hepatocellular adenoma/carcinoma (males) were seen. In a subchronic inhalation toxicity study in rats, pulmo nary

effects were observed at the mid and high doses. These effects included dose related increases in lung/bronchial weights and increased incidences of alveolar macrophages and peribronchiolar proliferation in both sexes.Fluazinam Human Health Risk Assessment DP No. D397601

Page 17 of 75 In a developmental toxicity study in rats , there was evidence of increased qualitative susceptibility

of fetuses to fluazinam; however, there was no evidence of increased quantitative susceptibility
. D ecrease d body weights, placental weights, and increased incidences of facial/palate clefts, diaphragmatic hernia and delayed ossification ( several bone ty pes ) were observed in fetuses at the HDT
. There was also greenish amniotic fluid and increases in late resorptions, as well as post
- implantation loss. Maternal effects observed at the same dose level were decrease d body

weight gain and food consumption, increase d water consumption, and increased urogenital staining. There was no evidence of increased quantitative or qualitative susceptibility in a developmental toxicity study in ra bbits or in a 2
- generation reproduction study in rats. In rabbits, increased incidences of total litter resorptions and a slightly increased incidence of fetal skeletal abnormalities (e
. g. kinked tail tip, fused or incompletely ossified sternebrae, and ab normalities of head bones) were seen in fetuses at the HDT. At the same dose, abortions, resorptions, placental anomalies, decreased body weight gain and food consumption, and significant liver histopath
ology were seen in maternal animals. Additionally , treatment - related effects were seen at lower doses in maternal animals in the absence of fetal effects. In the rat reproduction study, decreased pup weight gain was seen at the HDT in the presence of decreased food consumption and liver histopathology

in parental animals. Clinical signs were observed in an acute oral neurotoxicity study in rats ; decreases in motor activity and soft stools were seen on the day of dosing at the limit dose . These effects were attributed to sy stemic toxicity and were not co nsidered to be evidence of frank neurotoxicity . In two subchronic neurotoxicity studies (evaluated together) in rats , no evidence of neurotoxicity was observed up to and including the HDT
. A neurotoxic lesion described as vacuolization of the white matter of the CNS was observed initially in long
- term studies i n mice and dogs ; however, the lesion is reversible and was later attributed to the presence of an impurity in the technical material. The developmental neurotoxicity study was conducted with a technical with significantl y less of the impurity, and there were no lesions or developmental neurotoxicity concerns (see section 4.4.2)
. In an immunotoxicity

study in mice, significant suppressions of anti
- SRBC AFC assay response were demonstrated at the HDT indicating potential immunotoxicity . However, clear NOAELs and LOAELs were identified for the effects seen in the study and the points of departure (PODs) and end points selected for risk assessment are protective of immunotoxic effects. Fluazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” This classification was based on some ev idence of thyroid tumors in male rats and evidence of liver tumors in male mice. The CARC determined that quantification of risk using a non
- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity , that coul d result from exposure to fluazinam. Fluazinam (technical) has low or mild acute toxicity (Categories III and IV), except for acute eye irritation (I) and acute inhalation toxicity (II).Fluazinam Human Health Risk Assessment DP No. D397601

Page 18 of 75 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  The proposed and exi sting use patterns for fluazinam will result in dietary and residential exposure to infants and children. Thus, FQPA hazard and exposure considerations were addressed in HED’s evaluation of the database. HED recommends that the 10x FQPA Safety Factor ( for the protection of infants and children) be reduced to 1x. This recommendation is supported by

the following: 1) the t oxicological database for fluazinam is complete with regard to pre - and postnatal toxicity , including the required immunotoxicity and neurotoxicity

studies and the developmental neurotoxicity study , 2) the endpoints and doses selected for risk assessment are protective of the qualitative and quantitative susceptibility observed in the developmental rat and DNT studies , respectively , and the degree of concern for the susceptibility is low, 3) although indications of neurotoxicity and immunotoxicity

were observed in the database, there were clear NOAELs for these effects, and the endpoints and doses for risk assessment are protective of the potential effects, 4) the dietary exposure assessment s are based on high
- end health protective residue levels and processing factors for foods, and upper - bound assumptions were used to determine exposure through drinking water , and 5) the residential assessments were conducted in accordance with standard practices that ensure exposures were not underestimated , and further, no residential exposure is expected for children. **4.4.1 Completeness of the Toxicology Database**  The available toxici ty studies are adequate for assessing and characterizing potential pre
- and/or post - natal susceptibility for infants and children , and the database is complete in accordance with the Part 158 data requirements, including route
- specific toxicity studies
. Acceptable/guideline developmental toxicity

studies in rats and rabbit s, a reproduction study in rats , and a DNT study in rats are all available for FQPA assessment
. **4.4.2 Evidence of Neurotoxicity**  N o evidence of neurotoxicity was observed in an acute neurotoxicity study in rats up to 1000 mg/kg/day
. D ecreases in motor activity and soft stools were observed on the day of dosing. These findings are attributed to sy stemic toxicity and are not considered to be evidence of frank neurotoxicity
. However, a neurotoxic lesion described as vacuolization of the white matter of the central nervous s ys tem (CNS) was observed in subchronic and chronic studies in mice and dogs, as well as special studies in rats. After further investigation, it was determined that one single impurity , Impurity
- 5, was solel y responsible for the appearance of the white matter vacuolization . A developmental neurotoxicity (DNT) study

containing a lower concentration of Impurity- 5 was submitted to address the concerns regarding the vacuolization observed. In the study , there was no evidence of vacuolization of the brain or any other treatment
- related pathology up to the highest dose tested. The DNT study contained a lower concentration of Impurity- 5 than the maximum concentration of Impurity
- 5 in technical grade fluazinam. Therefore, it was concluded that fluazinam, per se , was not responsible for the induction of this lesion. A NOAEL for Impurity
- 5 was determined that is equivalent to a NOAEL for CNS effects of 20 mg/kg/day

for tec hnical grade fluazinam. The current acute and chronic reference doses selected for risk assessment are lower than the determined NOAEL and protective of any possible neurotoxic effects resulting from exposure to Impurity
- 5.Fluazinam Human Health Risk Assessment DP No. D397601

Page 19 of 75 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  No evidence of increased quantitative or qualitative susceptibility was seen in a developmental toxicity study in rabbits or a reproduction study in rats. However, there was eviden ce of i ncreased qualitative susceptibility of fetuses in the developmental toxicity study in rats. Increased incidences of facial/palate clefts and other rare deformities were seen in fetuses in the presence of minimal maternal toxicity . A DNT study in rats was submitted to address the increased susceptibility

as well as the presence of neurotoxic lesions observed after fluazinam exposure. In the DNT study , decreases in body weight and body

weight gain a s well as delayed
preputial separation were observe d in pups. These effects were seen in the absence of maternal effects, suggesting increased quantitative susceptibility of the offspring. Although there is evidence of increased qualitative susceptibility in the developmental toxicity study in rats, th ere are no residual uncertainties with regard to pre
- and/or postnatal toxicity following in utero exposure to rats or rabbits and pre and/or post
- natal exposures to rats. Considering the overall toxicity profile and the doses and endpoints selected for ri sk assessment, the degree of concern for the effects observed in the developmental rat study is low. There is a clear NOAEL for the fetal effects seen, the effects occurred in the presence of maternal toxicity , and they were onl y seen at the highest dose tested. Additionally , the fetal NOAEL of 50 mg/kg/day

identified in th e developmental toxicity study in rats is significantly

higher than the NOAEL used ( 7 mg/kg/day) to establish the acute reference d ose (aRfD , females 13
- 49); therefore, the aRfD is prot ective of any observed fetal effects. As previously

stated, i ncreased quantitative susceptibility was seen in the DNT study in rats
. Although the NOAEL determined for the DNT study (2 mg/kg/day) is lower than the NOAEL used for acute dietary

risk assessment for females 13
- 49 (7 mg/kg/day), the effects noted in the DNT study

are attributable to multiple doses and are considered to be post - natal effects. Therefore, the study endpoint is not appropriate for assessing acute dietary exposure and risk
. Additionally , the NOAEL (1.1 mg/kg/day) used for the chronic dietary assessment is lower, and is considered to be protective of the effects observed in the DNT study
. **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties with respect to dietary and residential exposure. The dietary exposure assessment s are based on high
- end health protective residue levels (that account for parent and metabolites of concern), and processing factors. Actual risk from exposure to fluaz inam will likely

be much lower than HED’s risk estimates conducted for the proposed and existing uses
. Furthermore, conservative, upper
- bound assumptions were used to determine exposure through drinking water and residential sources, such that these expos ures have not been underestimated.Fluazinam Human Health Risk Assessment DP No. D397601

Page 20 of 75 **4.5 Toxicity Endpoint and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  The detailed description s of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.3 of this assessment
. For acute dietary

assessment for females 13
- 49 , the endpoint selected for risk assessment was increased incidence of total litter resorptions and increased incidence of fetal skeletal abnormalities at the LOAELof 12 mg/kg/day , and the point of departure (POD) was the NOAEL of 7 mg/kg/day . For the general population, the acute dietary endpoi nt was clinical signs ( soft stools and decreased motor activity) observed at the LOAEL of 1000 mg/kg/day ; the POD was the study NOAEL of 50 mg/kg/day
. The effects observed in the selected studies are considered to be attributable to a single dose of fluaz inam
. For chronic dietary

exposure and risk assessment , the carcinogenicity study in mice and the chronic study in dogs were selected as co
- critical studies. In both studies, the NOAELs determined were approximately 1 mg/kg/day

and the LOAELs approximate ly 10 mg/kg/day . In the mouse, effects seen were mainl y in the liver ( increased pigmented macrophages , eosinophilic vacuolated hepatocy

tes , and liver weights). In dogs, nasal dry ness and gastric ly

mphoid hy perplasia were seen. The rat carcinogenicity study was also considered; however, the mouse and dog studies provided a lower point of departure. The POD for the chronic dietary assessment was the NOAELof 1.1 mg/kg/day from the carcinogenicity study in mice. For s hort
- and intermediate
- term dermal exposure, a refined dermal dose of 24.4 mg/kg/day was calculated based on the dermal toxicity study and dermal absorption data. In the dermal toxicity study , liver effects were seen at the LOAEL of 100 mg/kg/day
. Develo pmental effects were noted in developmental toxicity studies at ≥ 12 mg/kg/day . Although the RDD is 24 mg/kg/day , it is based on an oral NOAELthat is lower than the dose at which developmental effects were seen. The comparable dermal equivalent dose (DE D) for the developmental study , using the developmental NOAEL of 7 mg/kg/day and a DAF of 4.47% is 155 mg/kg/day . Therefore, the RDD is considered protective of potential developmental effects. Additionally , the RDD is protective of immunotoxic effects s een in an immunotoxicity study in mice at the LOAEL of 231 mg/kg/day
. For short
- and intermediate
- term inhalation exposure, a route - specific 4 week inhalation toxicity study was used for endpoint and dose selection
. Inprevious risk assessments, the sy st emic liver effects observed in a 7
- day inhalation study

served as the basis for endpoint and dose selection. However, i n the 4
- week study , a dose related increase in lung and bronchial weights in both sexes was observed at the LOAEL of 0.020 mg/L/day
. At 0.100 mg/L , there were also increased lung and bronchial weights, along with histopathology of the lung (alveolar macrophages, peribronchiolar proliferation) in both sexes. The NOAEL is 0.003 mg/L/day
. In accordance with current guidance, human equivalent concentrations (HECs) and human equivalent doses (HEDs) were calculated , with the HEDs being used for risk assessment. The occupational inhalation HED is 0.048 mg/kg/day , and the residential inhalation HED is 0.043 mg/kg/day
. The inhalation POD and en dpoint are protective of the developmental effects seen in rats as wellFluazinam Human Health Risk Assessment DP No. D397601

Page 21 of 75 as potential neurotoxicity and immunotoxicity since significantly lower PODs were determined in the inhalation study
. The occupational HED is based on an 8
- hour working day , and a corresponding 8 hours of inhalation exposure. The residential HED takes into account the potential for 24
- hour b ys tander exposure via the inhalation route. At the current time, there are no data to quantitatively assess inhalation exposure to residential by standers, and there are no other residential inhalation exposure scenarios based on the existing and proposed uses. If sufficient exposure data become available to assess potential by stander exposure and risk, the residential HED would be used. Based on the proposed use pattern for fluazinam , long
- term dermal and inhalation exposures are not anticipated. For acute and chronic dietary and dermal risk assessments, a 100 x uncertainty factor was applied (interspecies factor of 10 x and intraspecies f actor of 10 x ). For dietary assessments, the acute and chronic population adjusted doses are therefore For dermal risk assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined interspecies and intraspecies uncertai nty factors. For inhalation risk assessments, the LOC is an MOE of 30 (interspecies factor of 3 x and intraspecies factor of 10 x ) since human equivalent calculations (HECs) were used for risk assessment. The interspecies factor was reduced from 10 x to 3 x because the HEC calculation accounts for pharmacokinetic (not pharmacody namic) interspecies differenc es between animals and humans. **4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment**  When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: incidental oral, dermal , and inhalation . It must be determine d whether or not the individual exposures have the same toxicological effects. If they do, then they

can be combined. For fluazinam, inhalation and dermal routes cannot be combined because the t oxicological effects are different
. **4.5.3 Classification of Carcinogenic Potential**  In accordance with EPA’s Draft Guidelines for Carcinogen R isk Assessment (July, 1999), the Cancer Assessment Review Committee (CARC) classified (HED Doc. No.: 014512, March 29, 2001) fluazinam as having “ Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential , ” based on i ncreases in thy roid gland follicular cell tumors in male rats and increases in hepatocellular tumors in male mice
. Although there is evidence of thy roid tumors in male rats and liver tumors in male mice, the NOAEL used (1.12 mg/kg/day) for establishing th e chronic reference dose is approximately 3
- fold lower than the lowest dose that induced tumors (3.8 mg/kg/day). The Agency has determined that quantification of cancer risk using a non
- linear approach would adequatel y account for all chronic toxicity, in cluding carcinogenicity , that could result from exposure to fluazinam.Fluazinam Human Health Risk Assessment DP No. D397601

Page 22 of 75 The cancer classification is based on the following weight
- of
- evidence considerations: (i) There was some evidence that fluazinam induced an increase in thy roid gland follicular cell tumors in male rats, but not in female rats at ≥ 100 ppm (3.8 mg/kg/day). In one study in mice, there was clear evidence that an increased incidence of hepatocellular tumors observed in male mice was treatment
- related at 1000 ppm (107 mg/kg/day). In another study in mice, there was equivocal/some evidence that fluazinam might have induced an increase in hepatocellular tumors in the male mice at ≥ 3000 ppm (377mg/kg/day). Increases in hepatocellular tumors observed in the female mice in the latter study

were not statistically

significant , and some occurred at an excessively toxic dose level. The thyroid gland follicular cell tumors of concern were seen only in the male rats , and the hepatocellular tumors of concern were seen onl y in the male mice. (ii) Fluazinam was negative in mutagenicity assay s. In a combined chronic/carcinogenicity study in rats, increased incidences of thy roid gland follicular cell tumors were observed in male rats only . Additionally , i n two carcinogenicity studies in mice, increa sed incidences of hepatocellular tumors were observed in male mice only
. The CARC concluded that there was some evidence that the thyroid tumors observed in the male rats were treatment - related . For the liver tumors in mice, the CARC concluded that there was clear evidence of treatment
- related increases in both benign and malignant liver tumors in one study ; however, it was concluded that there was only equivocal/some evidence for hepatocellular tumors in the other study
. There was no evidence of mutagen icity in the available mutagenicity battery
. **4.5.4 Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Human**  **Health Risk Assessments**  **Table 4**  **.5 .**  **4. a.**  **Toxicological Doses and End points for Fluazinam** **for Use in**

**Dietary and Non -**  **Occupational H um**  **an Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD, Level of**

**Concern for Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (General population) NOAEL=

50 mg/kg/day **UF: 100 x** 

UF A= 10x UF H =10x FQPA SF=1x Ac ute RfD =0.5 mg/kg/day

aPAD= 0.5mg/kg/day Ac ute Neurotoxicity
- Rats. LOAEL = 1000 mg/kg/day based on decreased motor activity and soft stools on day of dosing. Ac ute Dietary (Females 13
- 49 years of age) NOAEL

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

UF A= 10x UF H =10x FQPA SF=1x Ac ute RfD =0.07

mg/kg/day aPAD = 0.07mg/kg/day Developmental Toxicity
- Rabbits. Developmental LOAEL = 12 mg/kg/day based on increased incidence of total litter resorptions and possibly increased incidence of fetal skeletal abnormalities.Fluazinam Human Health Risk Assessment DP No. D397601

Page 23 of 75 **Table 4**  **.5 .**  **4. a.**  **Toxicological Doses and End points for Fluazinam** **for Use in**

**Dietary and Non -**  **Occupational H um**  **an Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD, Level of**

**Concern for Risk Assessment**  **Study and Toxicological Effects** Chronic Dietary (All Populations) NOAEL=

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

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

mg/kg/day cPAD = 0.011mg/kg/day Co
- c ritical: Carcinogenicity
- Mice. LOAEL = 10.7 mg/kg/day based on liver histopathology and increased liver weight
. Chronic Dog. LOAEL = 10 mg/kg/day based on marginal increases in the incidence of nasal dryness in females and the incidence/severity of gastric lymphoid hyperplasia in both sexes. Dermal Short
- Term (1
- 30 days) Dermal NOAEL =

24.4 mg/kg/day **UF: 100 x** 

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

MOE = 100 21
- Day Dermal Toxicity
- Rats LOAEL= 100 mg/kg/day based on liver effects (increased AST and cholesterol levels). A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal POD and dermal absorption data (see A.2) Inhalation Short
- Term (1
- 30 days) NOAEL=

0.003 mg/L HEC= 0.0003 mg/L **HED = 0.043 m**  **g/kg/day UF: 30**  **x**

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

MOE = 30 4 week inhalation study in the rat. LOAEL = 0.020 mg/L based on a dose related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were also seen , along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both sexes. Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic

potential
. ” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed a dverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). PAD = p opulation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration; HED = human equivalent dose.Fluazinam Human Health Risk Assessment DP No. D397601

Page 24 of 75 **Table 4**  **.5 .**  **4. b**  **. Summ**  **ary of Toxicolog ical Doses and End**  **points for Fluazinam for Use in** 

**Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of Departure Uncertainty/**  **FQPA Safety Factors**  **Level of Concern for**

**Risk Assessment Study and Toxicological Effects**  Dermal Short
- Term (1
- 30 days); Intermediate

- Term (1
- 6 mo nths) Dermal NOAEL =

24.4 mg/kg/day UF=100 x

UF A=10x UF H =10x Occupational LOC for

MOE = 100 21
- Day Dermal Toxicity
- Rats LOAEL= 100 mg/kg/day based on liver effects (increased AST and cholesterol levels) A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal POD and dermal absorption data (see A.2) Inhalation Short
- Term (1
- 30 days); Intermediate

- Term (1
- 6 mo nths) NOAEL=

0.003 mg/L HEC= 0.001mg/L **HED =**  **0.048 mg** **/k g/day**  UF=30X

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

MOE = 30 4 week inhalation study in the rat. LOAEL = 0.020 mg/L based on a dose
related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both sexes.
Cancer (oral, dermal, inhalation) Classification: “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic

potential” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. HEC = human equivalent concentration; HED = human equivalent dose
. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and Animal Metabolism Studies**  The nature of fluazinam residues in plants is adequately understood based on metabolism studies on potatoes, peanuts, and grapes. The residue of concern in peanuts and root and tuber vegetables is parent fluazinam for purposes of both dietary risk assessm ent and tolerance enforcement (D272624, W. Cutchin, 4/23/2001) . For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment. For tolerance enforcement , the residues of concern in plants include fluazinam and AMGT for wine grapes, but onl y fluazinam for all other plant commodities.Fluazinam Human Health Risk Assessment DP No. D397601

Page 25 of 75 The nature of fluazinam residues in rotational crops is adequatel y understood. Based on the absence of metabolites containing the intact fluazinam nucleus , HED has determined that the residue of concern in rotational crops is the parent compound, and that rotational crop tolerances are not required for fluazinam. The available confined field rotational crop study supports the 30
- day plantback interval (PBI ) that is currentl y listed on the label for crops without direct uses of fluazinam. The nature of the residue in livestock is also understood based on acceptable goat and hen metabolism studies. The fluazinam residues of regulatory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates. **5.1.2 Summary of Environmental Degradation**  The environmental fate studies for fluazinam indicate that the parent compound forms transformation compounds that, in most cases, are similar in structure to the parent. Fluazinam does not undergo degradation. Instead, it undergoes transformation into a series of products, all of which are structurally

similar to the parent compound . For modeling drinking water residues, th e Environmental Fate and Effects Division (EFED) assumed that the phys icochemical characteristics were similar for both the parent and its products (i.e. , the total toxic residue approach). **5.1.3 Comparison of Metabolic Pathways**  Fluazinam is a secondary amine whose substituents are substituted phenyland py ridinyl ring s. The primary

metabolic and degradation pathway s involve reduction of nitro groups on the phenyl ring followed by

hydrol ys is or conjugation of the various substituents on both rings . Two of the primary

metabolites and degradates are AMPA and DAPA, and their hydrol ys is or conjugation products . These compounds are primary metabolites in plants, ruminants, poultry , drinking water, and rats. In plants, fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA. AMPA can then be conjugated with glutathione, with subsequent degradation of the glutathione moiety to cy steine. The AMPA
- cy steine conjugate then undergoes transamination, reduction, and conjugation with glucose to form AMGT. In addition, both rings of fluazinam appear to be labile to ring cleavage, and subsequent degradation of the rings into small fragments occurs. These fragments can then be incorporated into a variety of natural plant components. In ruminants and poultry , the metabolism of [ 14 C]
- fluazinam is comparable , and involves reduction of one or both nitro groups on the phenyl ring to form AMPA, MAPA, or DAPA. Fluazinam also undergoes dehalogenation and hydrox yl ation of the chlorine on the phenylring to form HYPA. These compounds can then undergo conjugation with glutathione, and subsequent degradation of the glutathione component yields a variety of polar compounds. Although the ring structure of the parent molecule remains intact, fluaz inam per se was onl y a minor component (≤2.7% TRR) of the [ 14 C]
- residues in poultry tissues and eggs, and was not detect ed in ruminant tissues or milk.Fluazinam Human Health Risk Assessment DP No. D397601

Page 26 of 75 In drinking water, the primary degradates include DCPA, CAPA, DAPA, HYPA, and AMPA. Although there are metabolites and degradates in plants, livestock, and drinking water that were not found in the rat, these compounds are structurally similar to the parent compound. The toxicity of these compounds is considered to be comparable to that of the parent. The toxicological endpoints that were selected for fluazinam are expected to be protective for the metabolites and degradates. **5.1.4 Residues of Concern Summary and Rationale**  HED has concluded that the residue of concern in peanuts and ro ot and tuber vegetables is parent fluazinam for purposes of both dietary risk assessment and tolerance enforcement (D272624, W. Cutchin, 4/23/2001) . For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes o f dietary risk assessment. For tolerance enforcement , the residues of concern in plants include fluazinam and AMGT for wine grapes, but only fluazinam for all other plant commodities. AMGT is included in the tolerance for wine grapes becaus e it is the on ly adequate measure of misuse for residues in wine. The parent does not serve as a misuse measure in wine because it degrad es during the fermentation process. Based on structural similarity, AMGT is assumed to have comparable toxicity as the parent and , therefore , is included for dietary

risk assessment in those crops where it is present at significant levels. Based on the absence of metabolites containing the intact fluazinam nucleus in rotational crop studies , HED has determined that the residue of con cern in rotational crops is the parent compound, and that rotational crop tolerances are not required for fluazinam. The available confined field rotational crop study supports the 30
- day plant
- back interval (PBI) that is currentl y listed on the label for crops without direct uses of fluazinam. The fluazinam residues of regulatory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates. These metabolites were the primary metabolites in the ruminant and poultry metabolism studies. AMPA and DAPA are structurally

similar to fluazinam. They are the products formed by reduction of one or both nitro groups on the phenylring to form the mono
- and di
- amino metabolites. Their toxicity is assumed to be compara

ble to that of the parent compound (D272624, W. Cutchin, 4/23/2001). **Table 5.1.4 .**  **Summary of Metabolites and D egradates to be included in the** 

**Risk Assessment and Tolerance Expression**  **Matrix Residues included in Risk**  **Assessment Residues included in**  **Tolerance Expression** Plants Primary Crop : grapes Parent fluazinam and AMGT Parent fluazinam and AMGT

Primary Crop : peanuts, root/tuber vegetables, bulb vegetables Parent fluazinam Parent fluazinam Primary Crop : all others Parent fluazinam and AMGT Parent fluazinamFluazinam Human Health Risk Assessment DP No. D397601

Page 27 of 75 **Table 5.1.4 .**  **Summary of Metabolites and D egradates to be included in the** 

**Risk Assessment and Tolerance Expression**  **Matrix Residues included in Risk**  **Assessment Residues included in**  **Tolerance Expression** Rotational Crop N/A Note: Tolerances are not required based on the absence of residues in rotational crops at the requested plant back interval. Livestock Ruminant Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Poultry Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Drinking Water Fluazinam, CAPA, DAPA, DCPA , HYPA, and AMPA Not Applicable
Under 40 CFR §180.574(a)(1), t olerances are established for residues of f luazinam, 3
- chloro
-N

- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl )
- 2
- py ridinamine ), including its metabolites and degradates, in or on the commodities in the table. Compliance with the tolerance levels is to be determined b y measuring only fluazinam. The existing tolerances for residues in grapes and livestock commodities are listed Under 40 CFR §180.574(a)(2) and (a)(3), respectivel y, including the relevant coverage and compliance statements. No changes are needed in conjunction with the proposed uses or to support registration review. **5 .2**  **Food Residue**  **Profile** The food use profile for the proposed and registered commodities is adequate and complete for tolerance setting and risk assessment purposes (D 397721, D. Dotson, 9 /7 /2012 ) . For so yb eans, melons, and peppers, the registrants submitted adequate field trial data for parent and the metabolite AMGT. For head and leaf lettuce, IR
- 4 sub mitted adequate field trial data for the metabolite AMGT , which were requ ested in a previous review ( D360840, D. Dotson, 3/31/2010 ). Adequate storage stability data were submitted for melons, peppers, and soy bean forage, hay , and seed. The data indicated that residues were stable over the storage durations used in the field trial and processing studies. For all crops, adequate numbers of trials were performed in the recommended NAFTA growing zones. Residues of parent fluazinam were below the LOQ of 0.0 1 ppm in all samples of soy bean seed. Quantifiable residues of fluazinam were found in soy bean forage, soy

bean hay , melons, and peppers. The ranges of residues in the samples of these commodities can be found in Table 5.2. No quantifiable residues of AM GT were found in any samples of any

commodities tested, including head and leaf lettuce.Fluazinam Human Health Risk Assessment DP No. D397601

Page 28 of 75 The registrant submitted a processing study for soybeans. Residues concentrated in soy bean hulls , and a separate tolerance for the commodity will be needed. Separate tolerances will not be needed for so ybean oil or meal. Although so ybean seed and hulls are livestock feed items, the current tolerances for livestock commodities (0.05 ppm for the fat and meat b yproducts of cattle, goats, horses, and sheep) are adequate. Table 5.2 provides a summary of the soy

bean, cantaloupe, pepper, and lettuce field trial data. **TABLE 5.2**  **. Summ ary of Fluazinam** **Field Trial Residue Data** Commodity Analyte Total Rate (lb ai/A) PHI

(days) Residue Levels (ppm) n Sample Min. Sample Max. LAFT 1 HAFT 2 Median Mean Std
. Dev. Soybeans Soybean Forage Fluazinam 0.99
- 1.17 29
- 35 16 0.021 3.73 0.034 3.06 0.427 0.63 0.74

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Soybean Hay Fluazinam 29
- 35 16 <0.017 5.21 0.028 5.21 0.868 1.41 1.48

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Soybean Seed Fluazinam 56
- 94 16 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Cantaloupes Cantaloupe Fluazinam 5.18
- 5.35 27
- 32 22 <0.01 0.077 <0.01 0.048 0.01 0.017 0.015

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Peppers (Bell and Non
- Bell) Bell Pepper Fluazinam 4.47
- 5.45 28
- 31 18 <0.01 0.038 <0.01 0.030 0.01 0.014 0.007

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Non
- Bell Pepper Fluazinam 5.10
- 5.29 28
- 31 8 <0.01 0.053 <0.01 0.045 0.01 0.02 0.016

AM GT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Lettuce Head Lettuce AM GT 0.95
- 1.02 46
- 52 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA Leaf Lettuce AM GT 0.97
- 1.05 20
- 32 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA 1 LAF T = lowest average field trial 2 HAFT = highest average field trial result. NA = not applicable The OECD MRLcalculation procedures were used for determining appropriate tolerance levels. The recommended tolerances for soy bean seed, soy

bean hulls, the melon subgroup, and the pepper/eggplant subgroup are listed in Table 2.2.3. **5.3 Water Residue Profile**  Th e drinking water assessment performed b y EFED provides E DWC s of fluazinam in surface water and in groundwater. The drinking water residue used in the dietary risk assessment was provided b y EFED ( D3 9 7602 , J. Meléndez, 7 / 17 /201 2 ) and incorporated directly into this dietary assessment into the food categories “water, direct, all sources” and “water, indirect, all sources .” The residues of concern in drinking water for risk assessment are parent fluazinam and itsFluazinam Human Health Risk Assessment DP No. D397601

Page 29 of 75 transformation products, including DCPA, CAPA, DAPA, HYPA, and AMPA. The acute and chronic EDWCs are based on ground application of fluazinam to turf. The turf use results in higher EDWCs than uses on the proposed crops (as well as all other crops). The values are provided in Table 5.3, below. The groundwater value was generated using the Screening Concentration in Groundwater (SCI
- GROW) Model and the surface water values were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model. The surface water estimates were used for both the acute and chronic assessments because they were higher than the groundwater value. For the acute assessment, a value of 226 ppb was used. This value includes both parent and degradates. For the chronic assessment, a value of 37.8 ppb was used. This value also includes both parent and degradates. For more information about EFED’s drinking water models, see http://www.epa.gov/oppefed1/ models/water
. **Table 5.3. Maxim um** **Tier 1 Estimated Drinking Water Concentrations Based on Ground**

**Application of Fluazinam to Turf at a Seasonal Rate of 8.4 lb a.i./A**  Source/Mo del Fluazinam Total Residues of Fluazinam 1 Acute/ppb Chronic/ppb Acute/ppb Chronic/ppb Surface Water/FIRST 217 2 1.47 **226** 2 **37.8** Groundwater/SCI
- GROW 0.404 **1.** Including the following transformation products: DCPA, HYPA, CAPA, DAPA , and AMPA. **2 .**  Exceeds the solubility of fluazinam at pH 7 (71 ppb), but not the solubility at pH 11 (350 ppm). **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM
- FCIDTM, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. The acute anal ys is is based on tolerance
- level residues for all commodities and uses high
- end residue estimates for the metabo lite AMGT. In addition, the acute assessment assumes 100% crop treated and incorporates modeled EDWCs that account for both parent fluazinam and its transformation products. D efault processing factors were used for all relevant processed commodities with out separate tolerances
. Therefore, the resulting exposure and risk estimates are considered to be very conservative. The chronic anal ys is is based on tolerance
- level residues for all commodities except apples. For apples, the average field trial value was used. As with the acute assessment, it incorporates high
end estimates for AMGT, 100% crop treated assumptions , d efault processing factors for all relevant processed commodities without a separate tolerance , and modeled EDWCs that account for both parent and transformation products. Again, the resulting exposure and risk estimates are considered to be conservative.Fluazinam Human Health Risk Assessment DP No. D397601

Page 30 of 75 Because such conservative assumptions were made in the assessments, the resulting exposure and risk estimates are considered to be conser vative as well. HED is confident that the acute and chronic dietary

exposure assessments significantly overestimate risk to the general U.S. population an d its various population subgroup s . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The acute and chronic assessments were both based on the assumption that 100% of all commodities with fluazinam tolerances will be treated. **5.4.3 Acute Dietary Risk Assessment**  The acute risk estimates at the 95 th percentile of exposure are below HED’s level of concern for all population subgroups, including those comprised of infants and children. Generally , HED is concerned when risk estimates exceed 100% of the population
- adjusted dose (PAD). The acute risk es timate for the general U.S. population is 5. 3 % of the acute PAD (aPAD). The population subgroup with the highest acute dietary risk estimate is Females 13
- 49, which uses 2 8 % of the aPAD. Although Females 13
- 49 use the greatest percent of the aPAD, the po pulation subgroup with the highest exposure estimate is Children 1
- 2. This subgroup uses 2 1 % of the aPAD. The reason this subgroup has a higher exposure but a lower estimated risk than Females 13
- 49 is that it has a higher aPAD value than Females 13
- 49 ( 0.5 mg/kg/day for Children 1
- 2 a s opposed to 0.07 mg/kg/day

for Females 13
- 49). Since the assessment used an assumption of 100 %CT, the risk estimates are being reported at the 95 th percentile of exposure. The acute dietary risk estimates are given in Table 5.4.6. **5.4.4 Chronic Dietary Risk Assessment**  Chronic risk estimates are also below HED’s level of concern for all population subgroups. The risk estimate for the general U.S. population is 20 % of the chronic PAD (cPAD). The most highl y exposed population subgroup is All Infants (<1 year old), which uses 51 % of the cPAD. The chronic dietary

risk estimates are given in Table 5.4.6. **5.4.5 Cancer Dietary Risk Assessment**  Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The CARC determined that quantification of risk using a non - linear approach (i.e., RfD) will adequatel y account for all chronic toxicity , including carcinogenicity , that could result from exposure to fluazinam. As a result, a separate dietary exposure assessment for cancer risk was not performed.Fluazinam Human Health Risk Assessment DP No. D397601

Page 31 of 75 **5.4.6 Summary Table**  **Table 5.4.6. Summary of Acute and Chronic Dietary**  **Ex posure and Risk Estimates for Fluazinam**  Population Subgroup Ac ute Assessment (95 th Percentile) Chronic Assessment aPAD, mg/kg/day Exposure Estimate,

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

mg/kg/day % cP AD U.S. Population 0.5 0.02 6393 5.3 0.011 0.00 2145 20 All infants 0.5 0.0 83776 1 7 0.011 0.004928 45 **Children 1 -**  **2 yrs** ***** 0.5 0. 106710 2 1 **0.011 0.005635**  **51** Children 3
- 5 y

rs 0.5 0.06 4022 13 0.011 0.00 3751 34 Children 6
- 12 y

rs 0.5 0.0 31323 6.3 0.011 0.00 2031 18 Youth 13
- 19 y

rs 0.5 0.01 7332 3.5 0.011 0.00 1171 11 Adults 20
- 49 y

rs 0.5 0.01 9148 3.8 0.011 0.001 936 18 Adults 50
- 99 y

rs 0.5 0.01 7495 3.5 0.011 0.00 2118 19 **Fem ales 13**  **- 49 yrs**  ***** **0.07 0.01**  **9721 2**  **8** 0.011 0.001 996 18 * The subpopulation s with the highest acute or chronic risk estimate s **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **6.1 Residential Handler Exposure**  **and Risk** The Agency

uses the term “Handlers” to describe those individuals who are involved in the pesticide application process. A residential handler assessment has not been conducted for fluazinam, since the end
- use product, Fluazinam Turf Fungicide , limits the application site to golf courses onl y . The proposed label also includes the following statement in the use restrictions section: “Do not apply product to home lawns (turf) or any other residential turf
. ” **6.2 Residential**  **Post -**  **a pplication Exposure**  Fluazinam residential post
- application scenarios include individuals playing golf on treated turf. C hildren 6 to <11 years ol d, youths 11 to <16 years old, and adults can potentially be exposed when they play

golf on treated turf

. Post
- application residential exposure was assessed using default assumptions and transfer coefficients from the HED SOPs for Residential Exposure Ass essments, (20 12 ), as well as chemical
- specific residue data from a turf transferable residue (TTR) study

(MRID No. 48361527)
. Although HED ty pically assesses oral (hand
- to - mouth) post - application exposure and risk for toddlers playing on treated turf, these exposures are not expected for golf course turf, and were therefore not assessed. **6.2.1 Dermal Post**  **- application Exposure**  Short
- term residential post
- application dermal exposures resulting in MOEs greater than or equal to 100 are not of concern. Sh ort - term dermal post
- application exposure and risk anal ys e s for golfers resulted in MOE s greater than the LOC and are not of concern. The highest risk estimate (lowest MOE) was for yo uth golfers aged 6 to <11 year s old, with an MOE of 780. A summary of the residential short
- term dermal exposure and risk estimates is shown in Table 6.2. 1
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 32 of 75 **Table 6.2.**  **1 .**  **Residential Post**  **- application Short**  **- term** **Derm al Exposure and Risk Estim**  **ate s**  **for Fluazinam Scenario**  **Application**

**Rate (lb ai/A)**  **TTR 1** 

**(μg/cm 2**  **) CF**  **T C** 

**(cm 2**  **/hr) ET** 

**(hrs) BW**  **(kg) Dose**  **2 (m**  **g/kg/day) Derm**  **al**

**MOE 3**  **Golfer** 6 to < 11 yrs old 0.7 0.0865 0.001 2,9 00 4 32 0.0 31356 780 11 to < 16 yrs old 0.7 0.0865 0.001 4,400 4 57 0.0267 09 9 1 0 Adult 0.7 0.0865 0.001 5,300 4 80 0.022923 1,100 1. Turf Transferable Residues (TTR) = 0.0865 ug/cm2 is based on predicted day 0 residue value calculated from chemical
specific data (MRID No. 48361527). 2. Dermal Dose (mg/kg/day) = [TTR (μg/cm2 ) x 0.001 (mg/μg) x TC (cm2/hr) x ET (hr/day)]/ BW (kg)
. 3. Dermal MOE = (NOAEL ( 24 .4 mg/kg/day) ) ÷ ( Dermal Dose (mg/kg/day) )
.
**6.2.2 Inhalation Post**  **- application Exposure**  Based on the Agency ’ s current practices, a quantitative post
- application inhalation exposure assessment i s not being performed for fluazinam at this time primarily because of its vapor pressure of 1.73 x 10 - 7 mm Hg . However, volatilization of pesticides can be a potential source of post - application inhalation exposure to individuals in close proximity to pesticide applications. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2 010 (http://www.epa.gov/scipoly /SAP /meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify

the need for and, subsequently , the way to incorporate post
- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency

m ight revisit the need for a quantitative post
- application inhalation expos ure assessment for fluazinam. **6.3 Combined Residential Risk Estimates**  HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneousl y based on the use pattern and when the toxicological effects are the same across different routes of exposure. Since inhalation post
- application exposure is expected to be negligible outdoors , and the application of fluazinam is only directed for golf course, incidental oral post
- application exposure for children i s also expected to be negligible. The only route of exposure is through the dermal route (i.e., dermal post
- application exposure)
. Therefore, combined residential exposure assessment for golfers i s not required
. **6.4 Residential Risk Estimates for Use in A**  **ggregate Assessment** The residential scenarios and risk estimates identified for use in performing an aggregate exposure assessment as part of the fluazinam human health risk assessment are: dermal post
application exposure resulting from treated golf cours es for adults (MOE = 1,100 ) and for children 6 to < 11 yrs old (MOE = 780).Fluazinam Human Health Risk Assessment DP No. D397601

Page 33 of 75 **6. 5**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents in close proximity to spraying operations. This is particularl y the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluazinam
. The Agency

has been working with the Spray Drift Task Force, EPA Regio nal Offices , State Lead Agencies for pesticide regulation , and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a ch emical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast , and ground hydraulic methods. After the p olicy

is in place, the Agency

m ight impose further refinements in spray drift management practices to reduce off
- target drift with specific products with significant risks associated with drift. Although a quantitative residential post
- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post
- application inhalation exposure scenarios
. **6. 6**  **Residential Bystander Post**  **- Application Inhalation Exposure**  Based on the Agency ’ s current practices, a quantitative post
- application inhalation exposure assessment is not being performed for fluazinam at this time primarily because of its vapor pressure ( 1.73 x 10 - 7 mm Hg ), and the proposed use rates (0.52
- 0.78 lb ai/A). However, volatilization of pesticides m ight be a source of post
- application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related t o volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post
application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are developed, the Agency m ight revisit the need for a quantitative post
- application inhalation exposure assessment for fluazinam
. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposure and risk estimate s from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estim ates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves canFluazinam Human Health Risk Assessment DP No. D397601

Page 34 of 75 be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute Aggregate Risk**  Acute aggregate risk result s from exposure to residues in food and drinking water. The acute dietary exposure anal ys is included both food and drinking water . Therefore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates , as discussed in Section 5.4.3, above. All risk estimates are not of concern. **7.2 Short**  **- /Intermediate**  **- Term Aggregate Risk Estimates**  For the short
- term aggregate risk assessment, the only relevant residential exposure scenario, dermal post - application , was combined with background exposure from food and water. The chronic dietary

exposure estimate s are the background exposure level s that w ere added directly to the residential dermal post
- application exposure estimate s . Of the population subgroups comprised of adults, the subgroup Adults 50
- 99 had the highest dietary exposure estimate. For the child and youth population subgroups, the dietary groups did not directly overlap with the representative residential life stages
. Specificall y, the closest dietary subgroup to the residenti al life stage children 6
- <11 was children 6
- 12, and the closest dietary subgroup to the residential life stage yo uth 12
- <16 was youth 13
- 19. The short
- term aggregate risk assessment s resulted in estimated MOE s of 7 30 to 9 7 0 . For fluazinam, the L OC for short
- term risk is an MOE of 100. As the resulting aggregate MOE s e xceed the LOC of 100, aggregate dietary and residential risk estimates are not of concern. Because the background exposure from food and water is so low relative to the dermal exposure estimates, the short
- term aggregate MOEs are the similar to those estimated for the dermal route alone. The aggregate risk estimates are given in Table 7.2. **Table 7.2. Residential**  **Short -** **/Intermediate -**  **Term Aggregate Risk Calculations**  Population Short
- or Intermediate
- Term Scenario NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average

Food and Water Exposure mg/kg/day Residential Post
application Dermal Exposure mg/kg/day 3 Total

Exposure 4 mg/kg/day Aggregate

MOE (food, water, and residential ) 5 Children 6
- <11 24.4 100 0.244 0.00 2031 0.031 356 0.033 3 87 7 30 Youth 11
- <16 24. 4 100 0.244 0.001 171 0.026 709 0.027 880 8 8 0 Adults 24.4 100 0.244 0.00 2118 0.0 2292 3 0.0 2 5041 9 7 0 1. An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x). No additional uncertainty factors/safety factors are required. 2
. Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3
. Residential Exposure = Dermal exposure from treated turf (see table 6.2.2). 4
. Total Exposure = Avg Food & Water Exposure + Residential Exposure 5
. Aggregate MOE = [NOAEL ( 24.4 mg/kg/day) ÷ ( Avg Food & Water Exposure + Residential Exposure ( mg/kg/day) ) ]Fluazinam Human Health Risk Assessment DP No. D397601

Page 35 of 75 **7. 3**  **Chronic Aggregate Risk** There are no residential scenarios that result in long
- term exposure. As a result, the chronic aggregate risk assessment result s from long
- term exposure to residues in food and drinking water only
. The chronic dietary expos ure anal ys is included both food and drinking water and, therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary assessment discussed in Section 5.4.4, above. All risk estimates are below HED’s level of concern. **7. 4**  **Cancer Aggregate Risk**  Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The CARC determined that quantification of risk using a non - linear approach (i.e., RfD) will adequatel y account for all chronic toxicity , including carcinogenicity , that could result from exposure to fluazinam. As a result, a separate dietary exposure assessment for cancer risk was not performed. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluazinam and any

other substances , and fluazinam does not appear to produce a toxic metabol ite produced b y other substances. For the purposes of this risk assessment , therefore, EPA has not assumed that fluazinam has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substanc es found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/
. **9.0 Occupational Exposure/Risk Characterization**  **9.1 Occupational Handler Exposure/Risk**  **Estimates** Based on the anticipated use patterns , current labeling, and the ty pes of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupation al handlers is based on the following scenarios:

• Mixing/L oading Liquids for Groundboom Application,
• Mixing/L oading Liquids for Aerial Application,
• Mixing/L oading Liquids for Chemigation,
• Applying Spray s with Groundboom Equipment,
• Applying Spray s with Aerial Equipment,
• F lagging for Aerial Applications, and
• M ixing/L oading/Applying L iquids with M echanically
- P ressurized H andgun S prayer.Fluazinam Human Health Risk Assessment DP No. D397601

Page 36 of 75 No handler exposures are expected from appl yi ng spray s via chemigation sy stems. The maximum s ingle application rate on the proposed label was used to assess all handler exposure scenarios ( 0. 52
- 0.78 lb ai/A) . The maximum application rate per acre per season ranges from 1.04
- 4.68 lb ai/A/y r. The number of applications per ye ar at the maximum single application rate ranged from 2
- 6 depending on the use site
. No data on the number of exposure day s per ye ar were provided. For fluazinam, based on the proposed use patterns and directions (e.g., 2
- 6 applications per season with a minimum 7
- 14 day spray interval depending on the use ), short
- and intermediate
- term exposures are expected for handlers. The estimates are considered to be protective for intermediate
- term exposure and risk
. Long
- term expos ures are not expected. Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The fluazinam product label directs mixers, loaders, applicators and other handlers to wear : baseline clothing (i.e., long
- sleeved shirt and long pants, socks), chemical
- resistant gloves and footwear , and protective eyewear. When mixing and loading , handlers must wear a chemical
resistant apron and a dust/mist filtering respirator (MSHA/NIOSH T C
- 21C) or a NIOSH approved respirator with an N, R, P or HE filter. Detailed descriptions of the occupational handler assessment are available in Z. Figueroa (D 397723 , 9 / 7 /2012 ) . The occupational hander exposure and risk estimates rely on generic data from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database. Some of these data are pro prietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures , ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/h andler
- exposure - table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at : http ://www.epa.gov/pesticides/science/handler
- exposure data.html In addition to the generic exposure data to assess occupational exposure and risk, HED used standard assumptions with respect to the area treated, the hours worked in a day , and the average adul t body

weight (80 kg). Occupational Handler Non
- Cancer Exposure and Risk Estimates Table 9 .1 presents the short
- term dermal and inhalation risk estimate s for handlers
. Since the endpoints selected for risk assessment are different for dermal (liver effects) and inhalation (lung effects) routes of exposure, the exposure and risk cannot be combined. Therefore, dermal and inhalation risks were calculated and presented sepa ratel y. Exposure estimates for the o c cupational handler scenarios described above resulted in MOEs greater than the respectiveFluazinam Human Health Risk Assessment DP No. D397601

Page 37 of 75 levels of concern (dermal L OC = 100; inhalation LOC = 30) at some level of PPE and with the assumption of an en closed cockpit (i.e., engineering controls ) for aerial applicato r s. Handler d ermal exposure and risk estimates were not of concern (LOC = 100) with baseline PPE , except for the following scenarios which required additional PPE to attain and MOE equal to o r greater than 100 ; however, HED notes that these additional PPE are already required on the proposed label :
 mixing/loading liquids for groundboom applications to soy beans , which require s the use of chemical
- resistant gloves,  mixing/loading liquids for aerial applications to soy beans , which require s the use of chemical
- resistant gloves + double layer clothing, and  mixing/loading liquids for chemigation for melons and peppers , which require s the use of chemical
- resistant gloves. Handler i nhalation exposure and risk estimates were not of concern (LOC = 30) at the baseline PPE (i.e., no respirator) for all of the scenarios. The dermal and inhalation handler risk estimates do not require any changes to the PPE listed on the proposed label. The Agency has evaluated scenarios that m ight be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantl y used as indicated b y the 1998 National Agricultural Aviation Association (NAAA) survey

of their membership. It appears, however, that flaggers are still used in approximately

10 to 15 percent of aerial application operations. In cases like these, the Agency strongl y encourages the use of the engineering contro l sy stem , but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and wil l consider those results as are timel y and appropriate. HED has no data to assess exposure for pilots using open cockpits. The only data available represent exposure for pilots in enclosed cockpits. Therefore, pilot exposure and risk estimates are deter mined assuming use of engineering control (enclosed cockpits) and baseline attire ( i.e., long
- sleeve shirt, long pants, shoes, and socks) . P ilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of co ncern for aerial applicators treating melons, peppers , and so ybeans with fluazinam in accordance with the proposed label.Fluazinam Human Health Risk Assessment DP No. D397601

Page 38 of 75 **Table 9**  **.1. Short -**  **Term Occupational Handler Exposure and Risk Estimates for Fluazinam Exposure Scenario**  **Crop or Target**  **Dermal Unit**

**Exposure ( μ**  **g/lb ai) 1**  **Inhalation Unit**

**Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area** 

**Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Mitigation Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Dose**  **(m g/k** **g/day) 6**  **MOE 7**  **Mixer/Loader** Li quids for Groundboom Applications (AHETF) Melons, Peppers 220 (Baseline) 0.219

(No respirator) 0.78 lb ai/A 80 A 0.171 140 0.000171 280 Soybeans 37.6

(Gloves) 0.219

(No respirator) 0.52 lb ai/A 200 A 0.0489 500 0.000285 170 Li quids for Aerial Application (AHETF) Soybeans 29.1 (Double Layer, Gloves) 0.219 (No respirator) 0.52 lb ai/A 1,200 A 0.228 110 0.00171 30 Li quids for Chemigation (AHETF) Melons, Peppers 37.6 (Gloves) 0.219

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

**Applicator** Sprays for Groundboom Applications (AHETF) Melons, Peppers 78.6 (Baseline) 0.34

(No respirator) 0.78 lb ai/A 80 A 0.061 400 0.000265 180 Soybeans 78.6

(Baseline) 0.34

(No respirator) 0.52 lb ai/A 200 A 0.102 240 0.000443 110 Sprays for Aerial Application (AHETF) Soybeans 5 (Engineering Controls
- Enclosed cockpit) 0.068

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

**Flagger** Flagging for Aerial Applications (PHED) Soybeans 11 (Baseline) 0.35

(No respirator) 0.52 lb ai/A 350 A 0.025 980 0.000796 60 **Mixer/Loader/Applicator** Mechanically
- pressurized Handgun Sprayer ( PHED ) Peppers (Soil

Drench) 1,300

( Baseline ) 3.9

(No respirator) 0.013 lb ai/gal 1,000 gal 0.211 120 0.000634 80
1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (Level of Mitigation: Baseline, Gloves, Double Layer, Eng. Controls). 2 Based on the proposed crops listed on the registered label ( EPA Reg . No. #71512
- 1)
. 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) x Applicati on Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW ( 80 kg). 5 Dermal MOE = Dermal NOAEL ( 24.4 mg/kg/day)/Dermal Dose (mg/kg/day) ; LOC = 100
. 6 Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai ) x Conversion Factor (0.001 mg/ μ g) x Application Rate (lb ai/A) x Ar ea Treated or Amount Handled (A/day or gal/day) /BW ( 80 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 0.048 mg/kg/day)/ I nhalation Dose (mg/kg/day) ; LOC = 30
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 39 of 75 **9 .**  **2 Occupational**  **Post -**  **application Exposure/Risk Estimates**  **9 .2.1**  **Occupational Post -**  **application Inhalation Exposure/Risk Estimates**  Based on the Agency ’ s current practices, a quantitative post
- application inhalation exposure assessment is not being performed for fluazinam at this time primarily because of its vapor pressure ( 1.73 x 10 - 7 mm Hg ), and the proposed use rates (0.52
- 0.78 lb ai/A). However , there are multiple potential sources of post
- application inhalation exposure to individuals performing post - application activities in previously
- treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.go v/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post
- application inhalation exposure data generated b y the Agricultural Reentry Task Force and m ight , as appropriate, develop p olicies and procedures to identify the need for and, subsequently , the way to incorporate occupational post
- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post
- application inhalation exposure assessment for fluazinam
. Although a quantitative occupational post
- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers , including flaggers . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post
- application exposure. Therefore, it is expected that these handler inhalation expos ure estimates would be protective of most occupational post
application inhalation exposure scenarios. **9 .**  **2 .2**  **Occupational Post -**  **application Dermal Exposure/Risk Estimates**  Occupational workers who enter treated fields to perform post
- application activities such as hand weeding and scouting m ight be exposed to fluazinam residues. Based on the use pattern, workers m ight be exposed to short
- and intermediate
- term exposure durations. Detailed descriptions of the occupational post
- application dermal assessment are available in Z. Figueroa, (D 397723 , 9 / 7 /2012 )
. Transfer Coefficients: Itis the policy of HED to use the best available data to assess post
application exposure. Sources of generic post
- application data, used as surrogate data in the absence of chemical
- specific data, are derived from ARTF exposure monitoring studies, and, as proprietary

data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post
- application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf ), which, along with additional info rmation about the ARTF data, can be found at : http://www.epa.gov/pesticides/science/post
app - exposure - data.html
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 40 of 75 Dislodgeable Foliar Residues : Chemical
- specific dislodgeabl e foliar residue (DFR) s tudies on apples (MRID#: 455842 03), potatoes (MRID # : 455842 02), and peanuts (MRID#: 45584201 ) were submitted and reviewed b y HED. The studies demonstrated that dislodgeable foliar residue values declined over time . Furthermore, H ED 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, d ermal post
- application exposure resulting from application of fluazinam on melons, peppers , and so yb eans was estimated using the best available surrogate DFR predicted Day
- 0 residue value from treated peanuts (0.987 ug/cm2 ) calculated b y a first
- order dissipation kinetics and decay model. Maximum single application rates were used in this assessment. Day
- 0 DFR values were adjusted b y application rate. Dermal exposures during post
- application activities were estimated using : 1) the maximum single application rate on the proposed label for each crop ( 0.52
- 0.78 lb ai/A ), 2) a standard body weight for the general population (80 kg), and 3) an average occupational workday of 8 hours per day
. Occupational Po st - application Non
- Cancer Dermal Risk Estimates A summary

of the post
- application exposure and risk estimates for the proposed uses is provided in Table 9 .2. b
. Only

risk estimates for the highest contact activity are shown below. Post
application dermal exposure and risk estimates for the scenarios shown below resulted in MOEs greater than 100 on the day of application, and are not of concern
. All other scenarios involving lower contact activities would have higher MOEs and are also not of concern. **Table 9**  **.2. 2.**  **b .**  **Short -**  **term Occupational Post**  **- application**  **Exposure and Risk Estimates for**  **Fluazinam Crop/Site**  **Activities DFR**  **1 Day 0 Dose**  **2 Day 0 MOE**  **3 Day at which**  **MOE ≥ LOC**  Melons Irrigation (hand set) 0.975 0.1850 130 0 Peppers Irrigation (hand set) 0.975 0.1850 130 0 Soybeans Scouting 0.650 0.0715 340 0 1
. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 ug/cm 2 is based on predicted day 0 residue value calculated from chemical
specific data (MRID No. 455842
- 01) and then adjusted by application rate. 2. Daily Dermal Dose = [DFR (μg/cm2 ) x TC x 0.001 mg/μg x 8 hrs/day]  BW (kg). 3. MOE = NOAEL (24.4 mg/kg/day) / Daily Dermal Dose. Restricted Entry

Interval The restricted entry

interval (REI) for fluazinam is based on the acute toxicity of technical material. Fluazinam is classified as Toxicity Category Ifor eye irritation. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute Toxicity Category Ifor any of the routes are assigned a 48
- hour REI. Based on the acute toxicity profile of fluazinam, the 48
- hour REI specified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post
- application exposures to fluazinam on melons, peppers , and soy beans.Fluazinam Human Health Risk Assessment DP No. D397601

Page 41 of 75 **10.0 References**  D. Dotson, K. Middleton, Z. Figueroa, 3 / 31 /201 0 , D365940 , Fluazinam. Human Health Risk Assessment for the Proposed Uses on Apples, Carrots, Lettuce, and the Bulb Onion Subgroup (3
- 07A), and a Request for a Reduced Tolerance on the Bushberry Subgroup (13
- 07B) D. Dotson, K. Middleton, Z. Figueroa, 2 / 7 /201 2, Fluazinam . Human Health Risk Assessment for the Section 3 Registration Action on Turfgrass D. Dotson, 9 / 7 /2 012 , Fluazinam. Petitions for the Establishment of Tolerances and Registration of New Uses on Soy

beans, the Melon Subgroup (9
- A), and the Pepper/Eggplant Subgroup (8
- 10B). Summary

of Analy tical 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 Soy beans, the Melon Subgroup (9A), and the Pepper/Eggplant Subgroup (8
- 10B) Z. Figueroa , 2 / 7 /2012 , D387284 , Flu azinam: Occupational and Residential Exposure Assessment for the Proposed Use on Golf Course Turf J. Melendez , 7 / 17 /201 2 , D3 9 7602 , Tier I Estimated Drinking Waters Concentrations of Fluazinam and its Transformation Products for the Use in the Human Health Risk Assessment for the Registration of the New Uses on Peppers, Eggplant (Subgroup 8
- 10B) , Melons (Subgroup 9A) , and Soy

beans Z. Figueroa, 9/7 /2012 , D397723 , Fluazinam: Occupational and Residential Exposure and Risk Assessment for Registration Re view and to Support the Registration of Proposed Uses on Melons, Peppers, and Soy beans W. Cutchin, 4/23/2001, D272624, Fluazinam . Decision by Metabolism Assessment Review Committee (MARC) D. Dotson, K. Middleton, S. Oonnithan, 9/2/2009, D 362190, Fluazinam Human Health Assessment Scoping Document in Support of Registration Review Fluazinam Final Work Plan for Registration Review , Fluazinam Registration Review Docket ID EPA
- HQ
- OPP
- 2009
- 0039 Y. Yang , 4/17/2012, D398060. Fluazinam : Immunotoxicity Study in Mice. K. Middleton , D393912 , Fluazinam: Toxicology Data Evaluation Record for Inhalation Toxicity StudyFluazinam Human Health Risk Assessment DP No. D397601

Page 42 of 75 **List of Appendices** Appendix A
. Toxicology Profile and Additional Data Appendix B. International Residue Limit Status Sheet Appendix C. F luazinam Phy sical/Chemical Properties Appendix D
. Review of Human Research Appendix E
. Structures of Fluazinam Metabolites and Degradates of Concern Appendix F
. Occupational Exposure and Risk Assessment t o Support Registration ReviewFluazinam Human Health Risk Assessment DP No. D397601

Page 43 of 75 **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 Ac ute 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 Ac ute 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 Ac ute 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 Ac ute eye irritation rabbits Technical grade fluazinam

(lot # SNPE B
- 1216, No. 1006; 97.9%) 42248606 Extremely irritating. Corneal opacity did NOT reverse in 21 days. I 870.2500 Acute dermal irritation rabbits Technical grade fluazinam

(lot # SNPE B
- 1216, No. 1006; 97.9%) 42248607 Slightly irritating IV 870.2600 Dermal sensitization guinea pigs Technical grade fluazinam

(lot # 1030/91; 96.7%) 42274401 Positive NA Ultra
-purified fluazinam (lot #Y910401; 100%) 42248608 Negative NA
**Table A.1.**  **2. Acu**  **te Toxicity Data on Fluazinam Guideline No./**  **Study Type Test Substance**  **MRID No. Results**  **Toxicity Category**  870.1100 Ac ute oral toxicity rats Omega 500F (40% fluazinam) 42974907 M: LD 50 >5000 mg/kg F: LD 50 >5000 mg/kg IV
870.1200 Ac ute dermal toxicity rabbits Omega 500F (40% fluazinam) 42974908 M: LD 50 >2000 mg/kg F: LD 50 >2000 mg/kg III
870.1300 Ac ute inhalation toxicity rats Fluazinam 50% WP a (51.3% fluazinam) 42311001 M: LC 50 = 3.0 mg/L F: LD 50 = 3.4 mg/L IV

870.2400 Ac ute 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 Omega 500F 42974912 Positive NAFluazinam Human Health Risk Assessment DP No. D397601

Page 44 of 75 **Table A.1.**  **2. Acu**  **te Toxicity Data on Fluazinam** sensitization guinea pigs (40% fluazinam)

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 uteru s 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) **Derm al**  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 **Developm ental**  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 boneFluazinam Human Health Risk Assessment DP No. D397601

Page 45 of 75 **Table A.1.**  **3. Subchronic, Chronic and Other Toxicity**  **Studies (Technical)**  **Guideline /**  **Type of Study Study Title/** 

**Classification /Doses MRID**  **Results** ty pes, 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) **Materna** l NOAEL = 4 mg/kg/day LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology. **Developm enta**  l NOAEL = 7 mg/kg/day LOAEL = 12 mg/kg/day based on an increase in total litter resorptions and possible fetal skeletal abnormalities 870.3700b Prenatal developmental toxicity rabbits F: 0, 0.3, 1, 3 mg/kg/day

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

LOAEL = not identified (>3 mg/kg/day) **Developm enta**  l NOAEL = 3 mg/kg/day LOAEL = not identified (>3 mg/kg/day) 870.3800 Reproduction and fertility effects rats F 0 males: 0, 1.5, 7.3,

36.6 mg/kg/day F 0 females: 0, 1.7, 8.4, 42.1 mg/kg/day F 1 males: 0, 1.9, 9.7, 47.3 mg/kg/day F 1 females: 0, 2.2, 10.6, 53.6 mg/kg/day Acceptable/guideline 42248619 (1987); 42208406 (1985); 42248618 (1986) **Parental/System ic**  NOAEL = 1.9

mg/kg/day LOAEL = 9.7 mg/kg/day based on liver pathology in F 1 males **Reproductive** NOAEL = 10.6 mg/kg/day LOAEL = 53.6 mg/kg/day based on decreased number of implantation sites and decreased litter size s to day 4 post
partum for F 1 females (F 2 litters). **Offspring** NOAEL = 8.4 mg/kg/day LOAEL = 42.1 mg/kg/day based on reduced F 1 and F 2 pup body weight gains during lactation. 870.4100a Chronic toxicity rats M: 0, 1.0, 1.9, 3.9

mg/kg/day F: 0, 1.2, 2.4, 4.9 mg/kg/day Acceptable/guideline 44839901 (1993); 44807213 NOAEL = Males: 1.9 mg/kg/day;

Females: 4.9 mg/kg/day LOAEL = Males: 3.9 mg/kg/day; Females: not identified (>4.9 mg/kg/day) based on increased testicular atrophy in males and no effects in fe males 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 Com bined 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. **Som e evidence of carcinogenicity** Fluazinam Human Health Risk Assessment DP No. D397601

Page 46 of 75 **Table A.1.**  **3. Subchronic, Chronic and Other Toxicity**  **Studies (Technical)**  **Guideline /**  **Type of Study Study Title/** 

**Classification /Doses MRID**  **Results (thyroid gland follicular cell tum**  **ors) in m**  **ale ra ts, but not in fem**  **ales**
. 870.4200b Carcinogenicity mice M: 0, 0.12, 1.1, 10.7,

107 mg/kg/day F: 0, 0.11, 1.2, 11.7, 117 mg/kg/day Acceptable/guideline 42208405 (1988); 4 4807220 (1996) NOAEL = Males:1.1 mg/kg/day;

Females: 1.2 mg/kg/day LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females **Clear evidence of carcinogenicity (hepatocellular tum**  **ors) in male m ice,**  **but not in fem ales**  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 tum**  **ors) in male mice, but not in fem**  **ales** 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 cy totoxic 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 cy totoxic 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
. Com pound tested to cytotoxic concentrations. 870.5300 In vitro mammalian Up to 5 μg/mL (+/
- S9) 45156902 (1986) Negative with and without S9 activation up to 5 μg/mL
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 47 of 75 **Table A.1.**  **3. Subchronic, Chronic and Other Toxicity**  **Studies (Technical)**  **Guideline /**  **Type of Study Study Title/** 

**Classification /Doses MRID**  **Results** gene mutation assay Acceptable/guideline Com pound 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 cy totoxic 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 Ac ute 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

wa s 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 48 of 75 **Table A.1.**  **3. Subchronic, Chronic and Other Toxicity**  **Studies (Technical)**  **Guideline /**  **Type of Study Study Title/** 

**Classification /Doses MRID**  **Results** 870.7600 Dermal Absorption
Rat 500 g/L (Fluazinam SC)

and 0.5 g/L (diluted Fluazinam SC) for 6 hours Acceptable/Guideline 48361513 (2001) The mean absorbed dose for Fluazinam SC at 24 hours was 0.38% (18.67 μg equiv.cm - 2 ). The dermal delivery was 0.52% (25.72 μg equiv.cm- 2 ). The mean absorbed dose for diluted Fluazinam SC at 24 hours was 4.08% (0.153 μ g equiv.cm - 2 ). The dermal delivery dose wa s 4.47% (0.169 μ g equiv.cm - 2 ). 870.7800 Immunotoxicity
Mouse Acceptable/Guideline

0, 1000, 3000 or 7000 ppm (0, 217.7, 679.0 or 1684.6 mg/kg/day) MRID 48708702 and 48708703 (2011) Under conditions of the combined

studies, the immunotoxicity NOAEL is 50 ppm (equivalent to 11 mg/kg/day); the LOAEL is 1000 ppm (equivalent to 231 mg/kg/day) based on decreased anti
- SRBC AFC response. The systemic toxicity NOAEL is 7000 ppm (168 4.6 mg/kg/day); the LOAEL wa s not established
. Non
- guideline In Vitro Percutaneous Absorption of Radiolabeled Fluazinam in T wo Form ulation s Through Rat Skin Fluazinam applied to 13

rat dermatomed skin membranes in vitro in 2 test formulations; Fluazinam SC and Diluted Fluazinam SC (Fluazinam Suspension using in vitro flow through diffusion cell system. The formulations were applied to skin for 24 hours at 10 uL/cm2 giving the nominal dose levels of 5000 μg/cm2 and 5 μg/cm. 2 48361514 (2000) Dermal delivery of Fluazinam from the Fluazinam SC (5000 μg/cm2 ) was 119 μg equiv/cm2 or 2.36% of the applied dose. Of this, only 58 μg equiv/cm2 or 1.16% of the applied dose was absorbed. Dermal delivery of Fluazinam from the Diluted Fluazinam SC (5 μg/cm2 ) was 1.88 μg equiv/cm 2 or 40.17% of the applied dose. Of this, only 0.75 μg equiv/cm2 or 15.95% of the applied dose wa s 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 T wo Form ulation 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 respectivel y. 48361515 (2000) Dermal delivery of Fluazinam from the Fluazinam SC was 81 ug equiv.cm 2 or 1.61% of the applied dose. Of this, only 8 ug equiv. cm2 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. cm2 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 0 50, 1000 and 3000

ppm for 7 days (0, 3.58, 71.1, and 212 48361509 (2004) Decrease in T4 and an increase or increasing trend in TSH at 1000 and 3000 ppm groups. Increase in UDPGTFluazinam Human Health Risk Assessment DP No. D397601

Page 49 of 75 **Table A.1.**  **3. Subchronic, Chronic and Other Toxicity**  **Studies (Technical)**  **Guideline /**  **Type of Study Study Title/** 

**Classification /Doses MRID**  **Results** Function in Rats mg/kg/day)

Acceptable/Non
- guide
line 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) I ncreases in cytochrome P
- 450 content, ECOD and PROD in the 1000 ppm group. The 100 ppm group showed an increase in ECOD and an increasing trend in PROD. Increases in CYP1A were seen in the 1000 ppm group. The 100 ppm group also exhibited an increase in CYP2B and an increasing trend in CYP1A. Hepatic proliferation in1000 ppm group after 7 and 14 days. No effect on oxidative stress markers. Non
- guideline Additional Mechanistic Study on Hepatic Drug
Metabolizing Enzyme induction, Cell Proliferation and th e Reversibility of its Toxic Effects in Mice Main: 0 and 1000 ppm

for 14 days and sacrificed (0 and 137 mg/kg/day) Recovery: 0 and 1000ppm (0 and 139 mg/kg/day) then reversibility for 14 days Acceptable/Non
- guide
line 48361512 (2005) Increases in P
- 450 PROD, ECOD after 14 days at 1000 ppm. Returned to normal in the satellite group after 14 days of recovery at 1000ppm. Increase in CYP1A and an increasing trend in CYP2B in the main group after 14 days at 1000 ppm. In the satellite group after 14 days at 1000 ppm, still a significant increase (but lower) in CYP1A. CYP2B returned to normal. No changes in hepatic proliferation observed in any group.Fluazinam Human Health Risk Assessment DP No. D397601

Page 50 of 75 **A. 2.**  **Triple Pack Analysis for Fluazinam** Using the available dermal a bsorption data for fluazinam, a refined dermal dose (RDD) for human skin was calculated. A RDD is calculated from a dermal point of departure (POD) and triple pack dermal absorption data ( in vivo rat, in vitro rat skin, and in vitro human skin) as follows: **R efined Dermal Dose (R** **DD )**  **=** Dermal Equivalent Dose (DED) x (animal in vitro  human in vitro **) POD=** **DED=Dermal NOAEL=** 10 mg/kg/day **RDD =** 10 mg/kg/day

x ( 40.17 %  16.49 %) = **24.4 mg/kg/day** Additional details of the study results supporting these calculations are shown in the table below:Fluazinam Human Health Risk Assessment DP No. D397601

Page 51 of 75 **Table A.2. Fluazinam** **Triple Pack Data Param**  **eters 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 Com parable exposure periods DED not required since dermal toxicity study used. Calculated a Refined Dermal Dose (RDD) to mo dify 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** Lo w (DSC)
-

24 hrs Hi (SC)
- 24 hrs Lo w (DSC) Hi (SC) Lo w (DSC) Hi (SC) 5 μ g/ cm

2 5000 μ g/ cm 2 5 μ g/ cm

2 5000 μ g/ cm 2 5 μ g/ cm

2 5000 μ g/ cm 2 **% Derm al**  **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. Lo ng - term dermal exposure not anticipated
. **Derm al**  **Equivalent Dose (DED)**  Dermal toxicity study was used for risk assessment (10 mg/kg/day).

Therefore, DED=POD=10mg/kg/day **Refined Derm**  **al Dose (based on**  **derm al**  **delivery values)**  **Diluted Suspension Concentrate (5 μ**  **g/ cm** **2 )** 

**POD=Dermal NOAEL=** 10mg/kg/day **DAF ( In Vivo**  **rat)=** 4.47% **In vitro human der**  **ma l 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 m g/kg/day** 

16.49%  **Inform ation taken from**  **“ Interim Guidance: Estim**  **ating Derm al Absorption Factors for Use In Human Health Risk**  **Assessments, Office of Pesticide Program s, June 2010**  **”**Fluazinam Human Health Risk Assessment DP No. D397601

Page 52 of 75 **A.3 HEC Inhalation Calculations**  In response to the data requirements for registration review, a 4 week repeated dose rat inhalation toxicity study

(MRID 48571410) was conducted to assess the effects of fluazinam via the inhalation route. Fluazinam was administered to 10/sex CD rats (nose only) for a total of 6 hours/day (two 3 hr exposures), 5 day s/week, as an aerosol with an average mass medium aerodynamic diameter (MMAD) of 4.7 and a geometric standard deviation (σ) of 2.7
. The LOAEL of 0.020 mg/L is based on a dose related increase in absolute and relative lung/bronchial weights in both sexes. The NOAEL is 0.003 mg/L. **RDDR for Fluazinam** Because the respired material used in the inhalation study is an aerosol, the RD DR ratio, which incorporates MMAD and σ, is appropriate to use for HEC calculation (table below)
. The “RDDR.exe” software program was used to obtain the RDDR value of 3.1 based on pulmonary effects as shown below. The inputs for the program are : MMAD =4.7; σ =2.7; BW for CD Rats from study

report=150g; S tandard human BW information (i.e., 70 kg).
**Table A.3. HEC Array for Non**  **- Occupational**  **and Occupational Risk Assessment** 

**Relevant Study LOAEL**  **(m g/** **L )**  **NOAEL**

**(m g/** **L )**  **Da Dh**  **Wa Wh**  **RDDR HEC**  **(m g/** **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 we ek) **(** MRID 48571410 ) **Pulmonary 0.020**  **0.003 6**  **24 5**  **7 0.486**  **0.0 003**  **3 10**  **NA**
**Long Term Exposure:** Not appropriate

**Key for Array Tables** LOAEL : Lowest observed adverse effect level Da : Daily animal exposure (hrs/day) Wa : Weekly animal exposure (days/week) RRDR : Regional Deposited Dose Ratio inter : interspecies extrapolation uncertainty factor Dh : Anticipated daily human exposure (hrs/day) Wh : Anticipated weekly human exposure (days/week) HC: Human Concentration HEC : Human Equivalent Concentration intra : intraspecies variation uncertainty factor UF: Other uncertainty factor(s)Fluazinam Human Health Risk Assessment DP No. D397601

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

Human Equivalent Doses Using the HEC s calculated , a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: D ose (s ys temic 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 p harmacody namic (PD) differences , the UF for interspecies extrapolation may be reduced to 3 x (to account for the PD differences between animals and humans which are not accounted for in the RfC methodology) while the UF for intraspecies variation is retaine d at 10 x . Thus, the UF when using the RfC methodology

is customarily

30 x . For fluazinam , HED believes exposures can be short
- (1
- 30 day s) or intermediate
- (1 to 6 months) term in duration. L ong - term exposures are n ot anticipated for fluazinam
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 54 of 75 For the short
- and intermediate
- term scenarios, inhalation data from the 4
- week inhalation rodent study was most appropriate for determining HECs. In the RfC methodology , different HECs can be calculated for the same experimental NOAEL because different algorithms are used to derive HECs for sy stemic versus port
- of
- entry effects. Ty

pically , HECs are calculated separatel y for sy stemic versus port
- of

- entry effect. For fluazinam , pulmonary effects were observed and , therefore, onl y pulmonary HECs were deri ved. 

### Ti me adjustments are traditionally needed for non - occupational (b ys tander) versus occupational exposure scenarios. Traditionally, HECs for non - occupational exposure are based on the number of hours an individual m ight be at home. Therefore, the mos t conservative estimate of hours spent at home would be 24 hours/day and 7 day s/week. In comparison, the average work week for an occupational worker is 8 hours/day and 5 day s/week. The HEC array table reflects the time adjustment in the calculations. **M ethodologies for Human**  **- Equivalent Concentration (HEC) Calculations.**  The RfC methodology

applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the phy sicochemical properties of the inhaled compound, the ty

pe of toxicity

observed ( e.g. sy stemic vs. port of entry) and the pharmacokinetic (PK) **but not pharmacodynamic** (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfC derivation is an es timate of the quantitative dose
- response assessment of chronic non
- cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species
- specific relationships of exposure concentration to deposited/delivered dose. This adjustment is influenced b y the phy sicochemical properties of the inhaled compound as well as the type of toxicity observed ( e.g. sy stemic 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 ty

pe of toxicity observed. Thus the derivation of a HEC for inhaled gases is described by the following equation:
Where: POD study : Point of departure identified in the critical toxicology study D animal exposure : Duration of animal exposure (hrs/day; day s/wk) D anticipated 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 aerodyn amic diameter [MMAD]) and the geometric standard deviation (σ g), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation par

ticulate exposure concentration of an animal (A) to the predicted 

## HEC = POD * D

D * W

W * RGDR study animal exp

osure (hrs / day) human expo

sure (hrs / day) animal exp osure (day s / wk) human expo

sure (days / wk)Fluazinam Human Health Risk Assessment DP No. D397601

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

r = (RDD r /Normalizing Factor) A (RDD r /Normalizing Factor) H As 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 specificall y for computing the RDDR from the MMAD and σ g defined from an aerosol inhalation study . The values for the species
- specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application o f Inhalation Dosimetry .”Fluazinam Human Health Risk Assessment DP No. D397601

Page 56 of 75 **A. 4**  **. Hazard Identification and Endpoint Selection**  **Acute Reference Dose (aRfD) -**  **Females age 13 -**  **49 Study Selected:**  Developmental T oxicity S tudy in 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 possibl e 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 a ppropriate for this population.

**Acute RfD (fem ales 13**  **- 49)**  = ) ( 100 / / 7 UF day kg mg = **0.07 m g/kg/day**  **Acute Reference Dose (aRfD) -**  **General Population Study Selected:**  Acute N eurotoxicity S tudy 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 an d endpoint for establishing the aRfD of 0.5 mg/kg/day . The NOAEL of 50 mg/kg/day

and the LOAELof 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 e xposure are appropriate for this population. **Acute RfD (fem ales 13**  **- 49)**  = ) ( 100 / / 50 UF day kg mg = **0.5 m g/kg/day** Fluazinam Human Health Risk Assessment DP No. D397601

Page 57 of 75 **Chronic Reference Dose (cRfD) Studies Selected:**  A 2
- y ear carcinogenicity study in mice and a 1
- 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
- ye ar 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 regularl y 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 dry nes s in females and increased incidence/severity of gastric ly mphoid hy

perplasia in males and females
. The NOAELs in the mouse (1.12 mg/kg/day in males and 1.16 mg/kg/day in females) and the dog (1 mg/kg/day in males and females) studies and the LOAELs in th e mouse (10.72 mg/kg/day in males and 11.72 mg/kg/day in females) and dog (10 mg/kg/day

in males and females) studies were similar. **1 st**  **Study:** 2
- Year C arcinogenicity S tudy in M ice **MRID No s**  **:** 42208405, 44807220, 44807212 **Dose and Endpoint for Risk Assessment**  : NOAEL= 1.12 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA Safety Factor) **Study/Endpoint/Uncertainty Factors:** A 2
- 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 hepatocy tes in males, and increased liver weights in females **.** The route and duration of exposure are appropriate for this population. **2 nd**  **Study:** 1
- Year C hronic O ral T oxicity S tudy in D ogs **MRID No s**  **:** 42270603, 44807219 **Dose and Endpoint for Risk Assessment** : NOAEL= 1 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA safety factor) **Study/Endpoin t/Uncertainty Factors:**  A 1
- 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 dry ness in females and the incidence/severity of gastric ly mphoid hy

perplasia in both sexes. The route and duration of exposure are appropriate for this population.
**Chronic RfD** = ) ( 100 / / 1
. 1 UF day kg mg = **0.011 m g/kg/day** 
**Comments:** A 2
- ye ar chronic feeding/carcinogenicity study in rats (MRID 42248620, 44807223) was also considered for establishing the cRfD based on a lower NOAEL of 0.38 mg/kg/day . The next highest dose level tested in this study was 3.8 mg/kg/day

in males and 4.9Fluazinam Human Health Risk Assessment DP No. D397601

Page 58 of 75 mg/kg/day

in females (a 10 fold higher dose). A second 2
- ye ar chronic feeding study in rats (MRID s 44839901 and 44807213) was subsequently performed with 2 intermediate dose levels. The doses used in the study were 0, 1.0, 1.9, and 3.9 mg/kg/day for male s; 0, 1.2, 2.4, and 4.9 mg/kg/day

for females. The NOAEL observed in the second study was 1.9 mg/kg/day

for males and 4.9 mg/kg/day

for females, which is higher than the NOAEL (1.1 mg/kg/day) selected for establishing the chronic RfD. Therefore, this stu dy was not chosen for risk assessment. **Dermal Exposure (Short -**  **, Intermediate -**  **Term) Stud**  **ies Selected:**  21
- Day D ermal T oxicity S tudy in Rats , In Vivo Dermal Penetration Study in Rats, and In Vitro Dermal Penetration Study in Human and Rat Skin **MRID No s**  **:** 42270602 , 48361513
- 15 **Dose and Endpoint for Risk Assessment** : Refined human dermal NOAEL= 24.4 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA Safety Factor) **Study/Endpoint/Uncertainty Factors:** A 21
- day dermal toxicity study in rats was used , along with dermal absorption data to refine the point of departure for short
- and intermediate
- term dermal risk assessment
. In the dermal toxicity study , 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 NOAELthat is lower than the dose at which developmental effects were seen. The comparable dermal equivalent dose (DED) for the developmental study , using the developmental NOAEL of 7 mg/kg/day and a DAF of 4 .47% is 155 mg/kg/day . Therefore, the RDD is considered protective of potential developmental effects. Additionally , the RDD is protective of immunotoxic effects seen in an immunotoxicity

study in mice at the LOAEL of 231 mg/kg/day
. **Inhalation Exposure (Short**  **- , Intermediate**  **- Term)**  **Study Selected:** 4 Week Inhalation Study in Rats (test material: Frowncide WP, containing 51.9% fluazinam) **MRID No:** 48571410 **Dose and Endpoint for Risk Assessment** : NOAEL= 0.003 mg/kg/day **Uncertainty Factor:** 30x (3x interspecies extrapolation, 10x intraspecies variability , 1x FQPA Safety Factor) **Inhalation absorption factor (IAF):** 100% **Study/Endpoint/Uncertainty Factors:** A 4 week inhalation study in rats was used to select the dose and endpoint for short
- and intermediate
- term inhalation exposure. The NOAEL of 0.003 mg/L and the LOAEL of 0.020 mg/L based on a dose related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L , increased lung/bronchial weights wereFluazinam Human Health Risk Assessment DP No. D397601

Page 59 of 75 also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both sexes. **Occupational and Residential Long**  **- Term Dermal and Inhalation Exposures**  Based on the proposed use pattern for fluazinam , long
- term dermal and inhalation exposures are not anticipated.Fluazinam Human Health Risk Assessment DP No. D397601

Page 60 of 75 **Appendix B. International Residue Limit Status Sheet Table B.1.**  **Summ ary of U**  **. S**  **. and International Tolerances and Maxim**  **um Residue Limits**  Residue Definition : US Canada Mexico 2 Codex [40 CFR § 180.574 (a)(1)] Plant: fluazinam ( 3
- chloro
- N
- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoro
methyl)phenyl]
- 5
- (trifluoromethyl)
- 2
-pyridinamine ) 3
- chloro
- N
- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl)
- 2
-pyridinamine None
Commodit

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

US Canada Mexico 2 Codex Apple 2.0 Apple, wet pomace 5.0 Bushberry subgroup 13
- 07B 7.0 7.0 aronia berries, buffalo currants, Chilean guavas, currants, elderberries, European barberries, gooseberries, highbush blueberries highbush cranberries honeysuckle, huckleberries, jostaberries, lingonberries, lowbush blueberries, native currants, salal berries, saskatoon berries (juneberries), sea buckthorn Carrot, roots 0.70 Ginseng 4.5 Lettuce, head 0.02 Lettuce, leaf 2.0 Onion, bulb, subgroup 3
- 07A 0.20 Pea and bean, dried shelled, except soybean, subgroup 6C, except pea 0.02 0.02 Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cowpea seed, guar seeds, kidney beans, lablab beans, lima beans, moth beans, mung beans, navy beans, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans); grain lupin Pea and bean, succulent shelled, subgroup 6B, except pea 0.04 Peanut 0.02 Potato 0.02 0.02 Turnip, greens 0.01 Vegetable, Brassica leafy, group 5 0.01 0.01 bok choy Chinese cabbages, broccoli, broccoli raab, Brussels sprouts, cabbages, cauliflower, Chinese broccoli, chinese mustard cabbages, collards,, kale, kohlrabi, mustard greens, mustard spinach, napa Chinese cabbages, rape greens Vegetable, legume, edible
podded, subgroup 6A, except pea 0.10 0.1edible podded ( jackbeans, moth beans, runner beans, snap beans, soybeans, sword beans, wax beans, yardlong beans) Proposed MRLs Melon subgroup 9A 0.08 Pepper/Eggplant Subgroup 8
- 10B 0.10 Soybean, Seed 0.01 0.1 edible
- podded soybeans Soybean, Hulls 0.05Fluazinam Human Health Risk Assessment DP No. D397601

Page 61 of 75 **Table B.1. Summ**  **ary of U .**  **S .**  **and International Tolerances and Maxim um** **Residue Limits** Residue Definition : US Canada Mexico 2 Codex [40 CFR §180.574(a)(2)] fluazinam and its metabolite AMGT (3
- [[4
- amino
- 3
- [[3
- chloro
- 5
- (trifluoromethyl)
- 2
- pyridinyl]amino]
- 2
-nitro
- 6
- (trifluoromethyl) phenyl]thio]
- 2
- (beta
- D
- glucopyranosyloxy) propionic acid). Same as above None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Grape, wine 1 3.0 [40 CFR §180.574(a)(3)] Canada Mexico 2 Codex fluazinam, AMPA (2
- (6
- amino
- 3
- chloro
- α,α,α - trifluoro
- 2
-nitro
-p toluidino)
- 3
- chloro
- 5
- (trifluoromethyl) pyridine), DAPA (3
- chloro
- 2
- (2,6
- diamino
- 3
- chloro
α,α,α. - trifluoro
-p - toluidino)
- 5
- (trifluoromethyl)pyridine), and their sulfamate conjugates. Same as above None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Cattle, fat 0.05 Cattle, meat byproducts 0.05 Goat, fat 0.05 Goat, meat byproducts 0.05 Horse, fat 0.05 Horse, meat byproducts 0.05 Sheep, fat 0.05 Sheep, meat byproducts 0.05 Proposed MRLs Milk 0.01 Meat of Cattle, Goat, Horse, and Sheep 0.03 Meat Byproducts of Cattle, Goat, Horse, and Sheep 0.10 Completed: : M. Negussie; 08/03/2012
1 No US registration as of March 15, 2002 (grape, wine)
. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Fluazinam Human Health Risk Assessment DP No. D397601

Page 62 of 75 **Appendix C**  **. Fluazinam**  **Physical/Chemical Properties**
**Table B.1. Physicochem** **ical Properties of Fluazinam**

**Param eter**  **Value Reference**  Melting Point/Range 115 .5 °C MRID 42208401 pH 5.85 MRID 43521001 Density (2 0 °C) 1. 74 g/cm3 MRID 42208401 Water Solubility (25°C) (pH 5 .5): 25 ppb (pH 7) : 71 ppb (pH 11 ) : 350 ppm MRID 42208401 Solvent Solubility (25°C) Solvent Solubility (g/L ) MRID 42208401 acetone dichloroethane ethyl acetate ethyl ether hexane methanol toluene 645 485 624 168 6.7 1 6 2 51 2 Vapor Pressure (25°C) 1.7 3 x 10 - 7 mm Hg ( 2.3 x 10 - 5 Pa) LSS 2000_1973_2LS_rev Dissociation Constant (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, 482Fluazinam Human Health Risk Assessment DP No. D397601

Page 63 of 75 **Appendix D**  **. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Datab ase Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re
- entry Task Force (ARTF) database; and other registrant
submitted studies (MRID Nos. 46991302, 45584203, 45584202 , and 48361527); are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies , that review m ight have included review b y the Human Studies Review Board. Descriptio ns of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler
- exposure - data.html and http://www.epa.gov/pesticides/science/post
- app - exposure - data.html
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 64 of 75 **A ppendix**  **E : Structures of Fluazinam Metabolites and Degradates of Concern** 
**Table E. 1.**  **Structures of Fluazinam Metabolites and Degradates of**  **Concern** Com pound Common N ame Structure
Fluazinam

AMGT Plant Metabolite

AMPA Livestock Metabolite Drinking Water Degradate

DAPA Livestock Metabolite Drinking Water Degradate Cl N H

C F 3 N O 2 O 2 N N Cl F 3 C

O O H O H O H O H O N H

C F 3 O 2 N N Cl F 3 C

N H 2 S HO O C

Cl

N H

C F 3 O 2 N N Cl F 3 C N H 2

Cl N H

C F 3 N Cl F 3 C N H 2 N H 2Fluazinam Human Health Risk Assessment DP No. D397601

Page 65 of 75 **Table E. 1.**  **Structures of Fluazinam Metabolites and Degradates of**  **Concern** Com pound Common N ame Structure
CAPA Drinking Water Degradate

DCPA Drinking Water Degradate

HYPA Drinking Water Degradate N H N

O 2 N O 2 N

Cl CF 3 Cl

HOOC

N H N O 2 N

COOH Cl O 2 N Cl

HOOC

DCPA

N H N O 2 N

CF 3 HO O 2 N Cl

F 3 CFluazinam Human Health Risk Assessment DP No. D397601

Page 66 of 75 **Appendix F. Occupational Exposure and**  **Risk Assessment to Support Registration Review** With the submission of the two toxicity studies required during registration review, as well as additional conditional data requested in conjunction with previously evaluated new use petitions, the toxicity and exposure database s 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 p roposed uses are taken into consideration. In addition, the largel y unrefined dietary assessments incorporated high end modeled estimates of drinking water exposure. The only potential residential exposure scenario results from dermal contact with treat ed golf course turf, and no dermal risks of concern were identified; the most recent policies and procedures for assessing residential exposure were used to estimate post
- application risk for yo uth and adult golfers. When these exposures were aggregated w ith background exposure from food and water, there were no aggregate risks of concern. In 2009 HED consulted the OPP Incident Data S ystem (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 require d to support the preliminary risk assessment. There were 5 major changes that required HED to reassess occupational exposure and risk for the existing uses of fluazinam, for the purpose of registration review: 1) The inhalation endpoint changed from s ys temi c liver effects to the portal
- of
- entry effects for the respiratory

s ys tem. Based on the results of the new inhalation study , the Reference Concentration methodology developed by

the Office of Research and Development (ORD) was used to calculate human equi valent concentrations (HECs) and doses (HEDs) for inhalation risk assessment ; 2) Since the effects observed via the inhalation route are different from the effects observed following dermal dosing, dermal and inhalation exposures are no longer combined in the risk assessment ; 3) HED has updated the surrogate unit exposures for occupational handlers, which have been incorporated in to the risk assessment for occupational handlers ( see Occupational Pesticide Handler Unit Exposure Surrogate Reference Table )
. **No changes to the label**Fluazinam Human Health Risk Assessment DP No. D397601

Page 67 of 75 **PPE , or other types of mitigation,**  **are required in conjunction with the revised risk estimates**  ; 4) HED has used an updated approach to incorporation of dislodgeable foliar residue (DFR) data ( i.e., use of predicted vs. measured day 0 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 ass umptions used for DFR studies, is presented in Z. Figueroa ( D 397723 , 9/7/2012)
. **Table F.**  **1. Summary of**  **Occupational Exposure Scenarios for Fluazinam** **Registered Uses EPA Reg.**  **No. Crop**  **Application Equipment Max.**  **rate/appl. (lb ai/A)**  **No. appl./season**

**(Re -**  **Treatm ent**  **Interval)**

71512
- 1 O me ga 500F (40% ai; 4.17 lb a.i. /ga l ) Dry

B ean & S ucculent Bean Crop Edible
-podded Legume Vegetables Groundboom 0.44 2 (7 days) Brassica vegetables (pre
- transplant soil spray band or bed ; post - transplant soil drench) Groundboom 1.36 (0.024 lb ai/gal) 1
- 2 (none) B ushberry Groundboom, airblast 0.65 6 (7 days) Carrots Groundboom, aerial, chemigation 0.52 4 (7 days) Lettuce Groundboom, a erial chemigation 0.78 1 (none) Onions Groundboom, aerial, chemigation 0.52 6 (7 days) Apples A erial , chemigation , airblast 0.45 10 (7 days) G inseng Groundboom 0.78 4 (7 days) P eanut s Groundboom 0.78 2 (21 days) P otato es Groundboom, a erial chemigation 0.26 7 (7 days) CO 070003 O me ga 500F P otato es

seed pieces (at
-plant in
- furrow over seed piece) Groundboom 1.8 1 (none) 71512
- 20 Fluazinam Turf Fungicide (40% ai; X) Turf (Golf Course) Groundboom, handheld (b ackpack , manually
-pressurized h andwand , and mechanically
pressurized h andgun sprayer s) 0.70 12 (14 days)Fluazinam Human Health Risk Assessment DP No. D397601

Page 68 of 75 **Occupational Handler Exposure and Risk Estimates** Based on the registered use patterns and current labeling, and the ty pes of equipment and techniques use for application, the following occupational handler exposures are expected from the registered uses. The quantitative exposure/risk assessment develop ed for occupational handlers is based on the following scenarios:

• Mixing/L oading Liquids for Groundboom Application,
• Mixing/L oading Liquids for Aerial Application,
• Mixing/L oading Liquids for Chemigation,
• Mixing/L oading Liquids for Airblast,
• Applying Spray s with Groundboom Equipment,
• Applying Spray s with Aerial Equipment,
• Applying Spray s with Airblast,
• Flagging for Aerial Applications,
• Mix er

/L oad er/Applicator for Mechanicall y- P ressurized Handgun Sprayer, • Mix er

/L oad er/Applicator for Backpack Sprayer, and
• Mix er

/L oad er/Applicator for Manuall y- pressurized Handwand No handler exposures are expected from appl yi ng spray s via chemigation sy stems. The maximum single application rate on the registered label was used to assess all handler exposure scenarios. No data on the number of exposure day s per ye ar 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, onl y 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 L OC = 30) at some level of PPE (e.g., c hemical
- resistant gloves, double l ayer clothing with chemical
- resistant h at) and assuming use of engineering controls (i.e., en closed cockpit) for aerial applications
. Based on the risk estimates shown below, no additional PPE or other mitigation is neede d on registered label s .Fluazinam Human Health Risk Assessment DP No. D397601

Page 69 of 75 **Table F.2. Short**  **- Term** **Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses**  **. Exposure Scenario**  **Crop or Target Dermal Unit**  **Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled 3**  **Dermal Inhalation**  **Mitigation Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Dose**  **(m g/k** **g/day) 6**  **MOE 7**  **Mixer/Loader**

Li quids for Groundboom Applications (AHETF) Turf (Golf Course) 220 (Baseline) 0.219

(No respirator) 0.70 lb ai/A 40 0.0770 320 0.000077 620 Potatoes (Spray) 220

(Baseline) 0.219

(No respirator) 0.26 lb ai/A 80 0.0573 430 0.000057 84 0 Potatoes (at plant in
- furrow over seed piece) 37.6 (Gloves) 0.219

(No respirator) 1.8 lb ai A 80 0.0676 360 0.00034 120 Dry Bean & Succulent Bean Crop, Edible
- podded Legume Vegetable 220 (Baseline) 0.219

(No respirator) 0.4 4 lb ai/A 80 0.0968 250 0.0000964 500 Carrots, Onions 220 (Baseline) 0.219

(No respirator) 0.52 lb ai/A 80 0.114 0 210 0.000114 420 Bushberry 220

(Baseline) 0.219

(No respirator) 0.65 lb ai/A 80 0.143 0 170 0.000143 340 Ginseng, Peanut s, Lettuce (Head and Leaf) 220

(Baseline) 0.219

(No respirator) 0.78 lb ai/A 80 0.171 0 140 0.000171 280 Brassica (Cole) Leafy Vegetables 37.6 (Gloves ) 0.219

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

Li quids 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 Li quids for Chemigation (AHETF) Potatoes 220 (Baseline) 0.219

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

Page 70 of 75 **Table F.2. Short**  **- Term** **Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses**  **. Exposure Scenario**  **Crop or Target Dermal Unit**  **Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled 3**  **Dermal Inhalation**  **Mitigation Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Dose**  **(m g/k** **g/day) 6**  **MOE 7**  Appl es 37.6

(Gloves ) 0.219

(No respirator) 0.45 lb ai/A 350 0.074 330 0.000431 110 Carrots, Onions 37.6 (Gloves ) 0.219

(No respirator) 0.52 lb ai/A 350 0.085 290 0.000499 100 Lettuce (Head and Leaf) 37.6

(Gloves ) 0.219

(No respirator) 0. 78 lb ai/A 350 0.1 29 190 0.000 748 60
Li quids for Airblast (AHETF) Apples 220 (Baseline) 0.219

(No respirator) 0.45 lb ai/A 40 0.0495 490 0.0000493 970 Bushberry 220

(Baseline) 0.219

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

**Applicato r** 

Sprays for Groundboom Applications (AHETF) Turf (Golf Course) 78.6 (Baseline) 0.34

(No respirator) 0.70 lb ai/A 40 0.02751 890 0.000119 400 Potatoes (Spray Treatment) 78.6 (Baseline) 0.34

(No respirator) 0.26 lb ai/A 80 0.0204 1 , 200 0.0000884 540 Potatoes (at plant in
- furrow over seed piece) 78.6 (Baseline) 0.34

(No respirator) 1.8 lb ai/A 80 0.141 170 0.000613 80 Dry Bean & Succulent Bean Crop, Edible
- podded Legume Vegetable 78.6 (Baseline) 0.34

(No respirator) 0.4 4 lb ai/A 80 0.0346 710 0.00015 320 Carrots, Onions 78.6 (Baseline) 0.34

(No respirator) 0.52 lb ai/A 80 0.0409 600 0.000176 270 Bushberry 78.6

(Baseline) 0.34

(No respirator) 0.65 lb ai/A 80 0.0511 480 0.000221 220 Ginseng, Peanuts , Lettuce (Head and Leaf) 78.6

(Baseline) 0.34

(No respirator) 0.78 lb ai/A 80 0.061 3 400 0.000265 180 Brassica (Cole) Leafy Vegetables 78.6

(Baseline) 0.34

(No respirator) 1.36 lb ai/A 80 0.1070 230 0.000463 100 Sprays for Aerial Application Potatoes 5 (Engineering Controls
- 0.068 (Engineering Controls
- 0.26 lb ai/A 350 0.00569 4 , 300 0.0000774 620Fluazinam Human Health Risk Assessment DP No. D397601

Page 71 of 75 **Table F.2. Short**  **- Term** **Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses**  **. Exposure Scenario**  **Crop or Target Dermal Unit**  **Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled 3**  **Dermal Inhalation**  **Mitigation Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Dose**  **(m g/k** **g/day) 6**  **MOE 7**  (AHETF) Enclosed cockpit) Enclosed cockpit) Apples 5

(Engineering Controls
- Enclosed cockpit) 0.068

(Engineering Controls
- Enclosed cockpit) 0.45 lb ai/A 350 0.00985 2,500 0.000134 360 Carrots, Onions 5

(Engineering Controls
- Enclosed cockpit) 0.068

(Engineering Controls
- Enclosed cockpit) 0.52 lb ai/A 350 0.01140 2,100 0.000155 310 Lettuce (Head and Leaf) 5

(Engineering Controls
- Enclosed cockpit) 0.068

(Engineering Controls
- Enclosed cockpit) 0. 78 lb ai/A 350 0.0171 1,400 0.0002 33 210
Sprays fo r Airblast Applications (AHETF ) Apples 1,480 (Double Layer + Chemical
- resistant Hat, Gloves) 4.71

(No respirator) 0.45 lb ai/A 40 0.333 500 0.00106 50 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 0.025 0 980 0.000796 60 Lettuce (Head and Leaf) 11

(Baseline) 0.35

(No respirator) 0. 78 lb ai/A 350 0.0375 650 0.0012 40 **Mixer/Loader/Applicator** Backpack Sprayer (MRID 44339801) Turf, Golf C ourse 826 0 (Baseline) 2
. 58 (Baseline) 0.0175 lb ai/gal 5 gals 0.00903 2,700 0.00000282 17,000 Manually
- pressurized Handwand (PHED) Landscape, Outdoor A reas 100 000

(Baseline) 30 (Baseline) 0.0175 lb ai/gal 5 gals 0.109 220 0.0000328 1,500 Mechanically
- pressurized Turf, Golf Courses 114 0 1
. 9 0.70 lb ai/A 5 A 0.050 490 0.0000831 580Fluazinam Human Health Risk Assessment DP No. D397601

Page 72 of 75 **Table F.2. Short**  **- Term** **Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses**  **. Exposure Scenario**  **Crop or Target Dermal Unit**  **Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled 3**  **Dermal Inhalation**  **Mitigation Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Dose**  **(m g/k** **g/day) 6**  **MOE 7**  Handgun Sprayer (Liquids) (ORETF) (Broadcast) (Baseline) (Baseline) Mechanically
- pressurized Handgun Sprayer (Liquids) ( PHED ) Brassica (Cole) Leafy

Vegetables (Soil Drench) 390

( Single Layer, Gloves) 3.9 (No respirator) 0.024 lb ai/gal 1,000 gal 0.117 210 0.00117 40
1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, Gloves, Eng. Controls). 2 Based on the registered labels (EPA Reg. No. 71512
- 1 and EPA Reg. No. 71512
- 20). 3 Exposure Science Advisory Council Po licy #9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated 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 = I

nhalation NOAEL (0.048 mg/kg/day)/ I nhalation Dose (mg/kg/day); LOC = 30.Fluazinam Human Health Risk Assessment DP No. D397601

Page 73 of 75 **Occupational Post** **- A** **pplication Exposure and Risk Estimates**  Post
- Application Inhalation Based on the Agency ’ s current practices, a quantitative non
- can cer occupational post
- application inhalation exposure assessment for the existing uses i s not being performed for fluazinam at this time; handler inhalation exposure estimates are considered to be protective of occupational post
application inhalation expo sure scenarios. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post
- application inhalation exposure assessment for fluazinam. Post
- Application Dermal S hort
- and intermediate
- term derm al exposures are expected for workers conducting post
application activities on agricultural crops. The standard values recommended for use in predicting post
- application exposure that are used in this assessment, known as “transfer coefficients , ” are pre sented in the ExpoSAC Policy 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/post
app - exposure - data.html
. Chemical
- specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203), potatoes (MRID 45584202), and peanuts (MRID 45584201) were submitted and reviewed b y 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 w ere available based on information about the study conditions, region of use, use pattern, etc. (M. Collantes, 03/18/2008, D3 49315). Therefore, the peanut DFR data w ere used as a surrogate t o assess dermal post
- application exposure resulting from application of fluazinam on ginseng, B rassica (cole) leafy

vegetables, succulent edible podded and dry beans, carrots, 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 b ased on the registered labels (EPA Reg. No. #71512
- 1 and EPA Reg. No. #71512
- 20). Residue valu es were adjusted by application rate, when applicable. Post
- application Exposure and Risk Estimate s – Agricultural Crops A summary

of the post
- application exposure and risk estimates for the registered agricultural uses is provided in Table F
. 3
.Fluazinam Human Health Risk Assessment DP No. D397601

Page 74 of 75 **T able**  **F .**  **3 . Short**  **- term** 

**Occupational Post -**  **application Exposure and Risk Esti mates**  **for Fluazinam Registered Uses**  **. Crop/Site**  **Activities DFR**  **1 (**  μg/cm2 **) Day 0 Dose**  **2**

(mg/kg/day) **Day 0 MOE 3**  **Day at which MOE ≥ LOC**  **DFR Data on Treated Peanuts (MRID 45584201)** Brassica (Cole) Leafy Vegetables Transplanting 1.70 0.0391 620 0

Scouting 1.70 0.0561 430 0 Hand Weeding 1.70 0.2380 100 0 Irrigation (hand set) 1.36 0.2580 100 2 Ginseng Weeding, Hand 0.975 0.0068 3,600 0

Scouting 0.975 0.0205 1,200 0 Harvesting, Hand 0.975 0.1070 230 0 Irrigation (hand set) 0.975 0.1850 130 0 Succulent Edible Podded and Dry Beans Hand weeding 0.550 0.00385 6,300 0

Scouting 0.550 0.01160 2,100 0 Scouting 0.550 0.06050 400 0 Irrigation (hand set) 0.550 0.10500 230 0 Carrots Hand Weeding 0.650 0.00455 5,400 0

Scouting 0.650 0.01370 1,800 0 Harvesting, Hand 0.650 0.0715 340 0 Irrigation (hand set) 0.650 0.1240 200 0 Bushberry Hand Weeding 0.812 0.00568 4,300 0

Transplanting 0.812 0.01870 1,300 0 Harvesting, Hand 0.812 0.08930 270 0 Irrigation (hand set) 0.812 0.1540 160 0
Lettuce Hand Weeding 0.975 0.00683 3,600 0

Scouting 0.975 0.02050 1,200 0 Transplanting 0.975 0.02240 1,100 0 Harvesting, Hand 0.975 0.10700 230 0 Irrigation (hand set) 0.975 0.18500 130 0 Onions Scouting 0.650 0.0215 1,100 0

Hand Weeding 0.650 0.0910 270 0 Irrigation (hand set) 0.650 0.1240 200 0 Weeding, Hand 0.582 0.2440 100 1 Peanuts Hand Weeding 0.975 0.0068 3,600 0

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

**DFR Data on Potatoes (MRID 45584202)** Potatoes Hand Weeding 0.232 0.00162 15,000 0

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

**DFR Data on Apple Trees (MRID 45584203)**

Apples Orchard

M aintenance , Propping, Hand Weeding, Thinning Fruit, Bird Control 0.017 0.00017 140,000 0 Transplanting 0.017 0.00039 62,000 0 Scouting, Hand Pr uning, Training 0.017 0.00099 25,000 0 Harvesting, Hand 0.017 0.00238 10,000 0 Thinning, Fruit 0.017 0.00061 4,000 0 1
. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 μ g/cm2 is based on predicted day 0 residue value calculated from chemical
specific data (MRID No. 455842 01) and then adjusted by application rate. Dislodgeable Foliar Residue (DFR) from Potatoes = 0.429 μ g/cm2 is based on predicted day 0 residue value calculated from chemical
- specific data (MRID No. 455842 0 2 ) and then adjusted by application rate. Dislodge able Foliar Residue (DFR) from Apples = 0.0471 μ g/cm2 is based on predicted day 0 residue value calculated from chemical
- specific data (MRID No. 455842 0 3 ) and then adjusted by application rate. 2. Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day]  BW ( 80 kg). 3. MOE = NOAEL (24.4 mg/kg/day) / Daily Dermal Dose.Fluazinam Human Health Risk Assessment DP No. D397601

Page 75 of 75 Short
- and intermediate
- term post - application risk estimates were not a concern on day 0 ( i.e., 12 hours following application) for most activities. Ba sed on HED’s post
- application exposure calculations, the following crops reached a dermal MOE of 100 within 48 hours of applicati o n , which is in accordance with the current label REI : • Onions resulted in a MOE of 100 or greater within 1 day (24 hours after application) for hand weeding activities; • Brassica ( c ole) l eafy v egetables resulted in an MOE of 100 or greater within 2 day s (48 hours after application) for irrigation (hand set) activities. The REI specified on the proposed label is based on the acute toxicity of f luazinam technical material
. Fluazinam is classified as Toxicity Category Ifor eye irritation. Under the Worker Protection Standard for Agricultural Pesticides, active ingredient s classified as acute toxicity category Ifor any of these routes are assigned a 48
- hour REI. Based on the acute toxicity profile of fluazinam, the 48
- hour REIspecified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post
- application exposures to fluazinam. Dermal Post
- appli cation Exposure and Risk Estimate

– Turf (Golf Course) Dermal post
- application exposure for turf was previously assessed ( D398546 , Z. Figueroa , 2/7/2012). A summary

of the post
- application exposure and risk estimate for turf is provided in Table F
. 4
. The p ost - application dermal exposure estimate resulted in an MOE greater than 100 and was not of concern. **Table F**  **. 4**  **. Short -**  **Term Occupational Post**  **- application Exposure and Risk Estim**  **ate Using Chemical -**  **Specific**

**Data for Fluazinam on Turf (Golf Course)**  **Crop/Site Activities**  **TTR 1**  **(** μg/cm2 **) Day 0 Dose**  **2**

(mg/kg/day) **Day 0 MOE 3**  **Day X at which MOE ≥**  **LOC** Turf/Sod Maintenance,

Harvesting, Slab Transplanting/ Pla nting 0.0865 0.0320 760 0 1. Turf Transferable Residue (TTR) = 0.0865 μg/cm2 is based on predicted day 0 residue value calculated from chemical
- specific data (MRID No. 48361527). 2. Chemical
- Specific Dermal Dose = [TTR ( μg/cm2 ) x TC (cm2/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, appl y when this product is used on agricultural crops . However, turf grasses on golf cours es are not within the scope of WPS. Therefore, HED concurs with the non
- agricultural use requirement listed on the label which states: “Do not enter or allow others to enter the area until treatments have dried.” The statement included in the proposed la bel is considered to be appropriate.