### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460 O FFI C E O F CHEMI C AL S A FETY AND POLLUTION PRE V ENTION



### ME MORAN DU M D a t e: S ubj ect:

F r o m :

T hro u g h :

To: 1-September

- 20 15 F lutri afo l: Hum an Health Ri sk Assess me nt in S upport of a Sectio n 3 Regi stration for Ap p licat ion to Hops.
PC Co d e: 128940 DP Barcode: 0 42 245 1 Dec i s io n No.: 492995 R eg i s tra ti o n No.: 67760-75 Pe titi o n No.: 4F8294 R eg ul ato r y Ac ti o n : Sectio n 3 Reg i stration Ri sk As sess m e nt Ty p e : aggregate Case No.: 7060 T XR No.: no t app l icable CAS No.: 76674-2 1

- 0 MR ID No: not app li cable 40 CFR: 18 0.629 Tom B loem,

# Ch**~** /) / Anwar Y. Dunbar, Ph.D
. . Pharm aco logi s t

### ~**~- J/~**  Kelly M. Lowe, E nv ironm e ntal Sc ienti s t / Risk Assessment Branc h I (RAB I ) Health Effects Di v is ion (HE D ; 7509 P )

Hope Johnson/Maryam K
. Muhammad , RM 21 Registration Di v i s ion ( RD ; 7505P) 

# 2<--

-- ------

HED of the Office of Pesticide Programs (OPP) i s charged w ith estima tin g the ri s k to human health from expos ure to pesticides. RD of OPP has reque s ted that H ED eva luate haz ard and ex po s ure data a n d conduct dietary , occupationa l , res idential , and agg regate expos u re assessments , as needed , to est ima te th e ri sk to human h ea lth tha t w ill re s ult from all registered and pro p osed u ses of flutriafol (( ± ) -a- (2- tluoroph e ny l) -a- ( 4-tluoropheny l )- 1 H

- 1 ,2 ,4-triazole

- l

ethano l) . A s u mmary of the fi n d ings and an as sess ment of human health r i s k res ul t ing from the registered and proposed u ses fo r tlutri afo l are provided in this document. The ri s k assess m e nt , dietary ri s k assessment , and r es idue chemistry rev iew we re provid ed b y Tom Blo e m (RAB I ), the hazard c haracterizatio n was provided by Anwar Dunbar (RAB 1 ) , the occupatio n al/residentia l ex po su re (ORE) w a s provided by Kell y Lowe 

### (RA B I ), a nd the drinking wa t e r assessment was provided by J ames K. Wolf of th e En v irorunent a l Fate and Effec t s Divi s ion ( EFED ).

Page I of3 IFl utri afo l H uman H ea lth Risk Assessme nt D42245 1 Tab l e of C ont e nts 1 .0 EXEC UT I VE SU MMA RY
...... . .. .. ................................................................................................. . ............. . ... 3 2.0 RECO M MEND AT IONS
......................................... . ............ ... .......... ... ............ .. ............ .. ........... .. . . ........... .. ... 5 2.1 Data Defic ienc ies/Data Needs
......................................................................... . ............ .. ............ .. ............ .. .... 5 2.2 T o l e ran ce Co ns id erat ion s ...... .. . ... . ... . .. . ........ ..... ..... . .. ..... . .. .. .. .. .......... ... ....... . .... .. ....... . .. . . .. ........ . .. .. ........... . ...... 6 2.2. 1 Enforcemen t Ana l yt i ca l Me th o d
............................... . ............ .. ....................................... .. . . ................ 6 2.2.2 R ecom mended Tole rances ........... .. ............ . ...................................................................... . ................. 6 2
. 2.3 R evis io n s to P e titi on ed-F o r Tol eran ces ........... ...... ....... ...... ......... .... ........ ...... .... . ....... .. ......... ... ............ .... .. 6 2
. 2.4 I n t

e rn ationa l H a nn o ni za tio n .. . ........... .. . . ......... .. . . ............. . ........................ .. .............. . .......... . . ... ............ .. ... 6 2.3 Label Recomme n dations
. .............. . ............ .. ...................................... . .............. . ............................................... 6 3. 0 3.1 3.2 3.3 3.4 IN G REDI E NT PROF ILE
.......... ... . . ........ ... . .. ..... ..... .. . ....... .... . . ........ .. .. .. ..... . . ........... . ........ .. .... .. ... ........ ...... ..... .. 7 Chemical I den tit y ................................................................. . ........... . ........... . .............................. . .................. 7 Propose d Use Patt ern . ..... .......... .. ........... ... ........ . .. .. ............................. . ........... . .. . ............ .. ............ . ........... . ..... 7 Ant ic ip ated Ex po s ure Pathw ays ................. . .. . ..... . .. ... . . ......... ... . . ....... . .. . ... .. . .. .. . ... ..... .. . .. .. . . . .. ..... ..... . . ..... . .. .... ... 8 Cons id eratio n of Environmen tal Jus tice
.............................. . ........................... . ............. . ............. . ............. .. ... 8 4.0 HAZA RD C HARA CTE RI ZA T ION AN D D OSE

- RES P ONSE ASSESS MENT
........ . .. .. ........... .. ................. 9 4. 1 Tox i co logy St udi es Ava il able fo r Ana l ys i s ...................................... .. . .. ........... . .. . ......... .... .......... . .............. . ... 9 4.2 Abso rp tion, Dis tr ibution, Metabolism , & Elimina ti on (ADME)
.................................... . ............ . .................. 9 4.2. 1 D e rmal Ab so rpti o n ......... .. ........... .. ............ .. ............ .. .. .. ........ . ............. .. . .. ....... .... . . .......... ... ............... 1 0 4.3 Tox ico log ica l Effects
.. .. .................. . ....... ... ............ .. ........... ... ........... . .. .. .......... .. ........... .. . .. ........ ... .......... ..... . . I0 4.4 Safety Fac tor fo r In fa nts and C h ildren (FQ P A SF)
......................................... .. ............ . ............................... 1 I 4 .4. 1 Co mp leten ess o f th e Toxico logy Database
.. ........................................ .. ........................................ . ... 1 1 4.4.2 Ev ide nc e ofNe uro tox i c ity
....................... ... ........... . ... . ....................... . .............. . ........... .. .......... . ........ 11 4.4.3 Evidence of Sensitivity / Susceptibility in th e Develo pi ng or Young Anima l.
.................................... I I 4.4.4 Res id ua l Unce rt a in ty in th e Ex po s ure Database
.... .. .......................... .. .............................................. 1 1 4.5 T ox i c ity E ndpo in t and Poi nt of D epa rture Se l ec t ions ...... .. .. .. ....................................... .. ........ .... .......... .... .... 1 2

5.0 4.5.1 Dose -Response Assessmen t
.......................................................................................................... . ... 12 4
. 5
. 2 R eco mm e n da ti o n fo r Co m b in ing R o ut es o f Expos ure for Ris k Assess men t..
.............................. . .... 13 4.5.3 Cance r C l ass ifi cat ion a nd Ris k Assess m e nt Reco mm end at ion ......... .... ......... .. .. .. ....... ...... ....... .... ..... 13 5. 1 5.2 5.3 5 .4 D IETA R Y EX P OSURE AND RJ S K ASSESSM E NT
........................ .. .......................................................... 15 Me t a bo li t e/ D eg rad ate R es idu e Profil e .. ....... ... . ... .. . .. .. .. ... .. .... .. . .. .. .. .. . . .. .. . ...... ...... .. . ..... .. . ... ......... ... .. . . . ....... . . . .. 15 Foo d R es id ue Profi l e .. . ............................ . ............. . ............. . ............ .. .......... .. . .. ......... .. . ... .......... .. ...... . .... . . . ... 16 Drinking Water Resid ue P rofile
.... . ................................................................... . ........................................... 16 Dietary (Foo d + Drinki ng Wat e r

) Risk A ssess m e nt
.. .......... .... ................................................... .. .......... .. ..... 17 6.0 RES ID ENT I AL (NON

- OCCUPAT I ONA L) EXPOSURE/RI S K C HARA CTE RI ZAT ION
.......................... 1 8 6. 1 Spray Dri ft
................................... . ........... ... ........... .. ............ .. ................................................... . .................... 18 6.2 R es id e nti a l Bys tan de r P o s t-A pp li cation Inh a lation Expos ure .. ............ .. ......... . ... .. ......... . ....................... .. ..... 1 8 7.0 AGG RE GA T E EXPOSURE / RJS K C H ARACTE RJ ZATION
............ . ........................................................... 19 8.0 CU MU LA T IVE EX PO S URE / RISK C HARA CTER I ZAT I ON
.. ....... . .. .. ......... ... .. .... ...... . .. .. ....... ......... ... .. .. .. . . 1 9 9.0 OCCU P AT I ONAL EX P OSURE / RI SK C HARAC T E RI ZAT I ON
.............................................. .. ................. 20 9
. 1 H andl e r Ri s k A ssess ment
.......... .. ............ . ............ ... ............ .. ....................... . ... . ...... . .. . .. . ............ .. .......... .. . .. .. 20 9.2 P ost-Appl ica ti o n Ri s k Assess ment
......... .. . .. ............. . ........ ... .. .. .......... . .......... ... .. . ......... .. ............ . .................. 20 9.2. I I nhalat ion Post
- App l icat ion Risk Assess men t
........ .. ....................................................... . ........... . ..... 20 9 .2.2 R es tr icted E n try l nt erva l
.. ....... . .. .. ............. . ....................... . ............... . . .. ........ .. .. .. .......... ... .. . ........ .. . . ... 22 AP PEND IX A. TOX I COLOG Y PR O FI LE AN D EXECUT I VE SU MM ARJ ES
.................................. . .. . ........... . .... 23 A PPEND IX B. C HEM I C AL NA M ES A ND S T RUCTU RE S
....... .. .. . ....... .. .. .. .......... ...... ......... .. . . ............ . ................ 29 APPEND I X C. PH YS I CAL/C HE MI CA L PR O PE R

T IES
. ............... . ............ .. ............. .. ...................................... . .... 3 1

Page 2 ofJ IFlutriafol Hum an H ea lth Ri s k Asse ss m ent 0422451 

### 1 .0 Exec u tive S umm ary Flutri afo l (( ± )-a

- (2-fl uor o phen yl) -a- ( 4-fluorophen y l) -lH-1 ,2,4- tri azo le- 1 -ethano l) i s a contact a nd syste mi c Group 3 tri azo le fun g ic id e whic h acts primarily as an inhibitor o f ergosterol biosynthes i s , thereby interfering w ith sy nth es i s of fungal ce ll membranes. T o leran ces fo r res idu es of flutriafo l are es tab l i s hed i n/on numerou s commod i t ies , in c ludin g l ive stoc k commodities , at 0.01-30 ppm. C hemino v a , Inc. reques t ed a Section 3 Registration an d the esta bli s hment of p e rmanent to lerances for re s id ues of fl u triafo l in / on hops. 

### H a zardAssessm e nt : Consistent with m a mm a lian tox icit y of th e other triazol e fun g ic i des, the effects in th e flutr iafo l d ata base are indicati ve of hepa totox ici ty. There were s light indicati o n s of e ffects in th e hematopo iet i c system. T he re i s no evidence of dermal toxicity , immunoto x icit y o r ca rc i n oge nici ty. Th e re i s ev id e n ce of in c rease d quantitati ve and qualitative pre - a nd po st natal s usceptibi lity fo r tlutria fo l in rat s and rabbit s. Flutriafol i s class ifi e d as " not likel y to be carc in oge nic to human s " based o n th e results of th e carcinogenicity studies in rats a nd rruc e . 

### Foo d Q u a lit y Pr o t ectio11 Act (FQ P A) Sa f ety Fa ct o r (SF) Decis i on : T h e fl u tr iafo l risk assessment team co nclud es that the I Ox FQP A SF sho uld be reduced to 1 x s ince th e to x ico lo gy database i s adeq u ate for assess me nt of the proposed/ regis t e red u ses, tlutr iafol i s no t considered to b e neurotoxic , th ere are cl ea r no-ob serve d adve rse -eff ec t levels (NOAELs) for the observed fetal/ offs prin g effec t s , and the conservat ive nature o f the dietary ex p osure a n a lyses a re un li kely to underes timate exposure (tolerance- lev e l re s idue s and 100 % crop tre ate d ; no res idential u ses)
. 

### Dose R es p o n se Assessm e nt : Tab l es 4.4 . l and 4
. 4.2 prov ides a s ummary of tox ico l og ica l dose s and e ndpo int s u se d fo r assessment of d ie tar y and occupational exposure , res p ec ti ve ly , to flutria fo l. The rabbit d eve lopm e ntal s tud y (N OA EL = 7.5 mg/ kg/da y) was se le c t e d for assessment of ac u te dietary (fe ma les 1 3-49 years old) and s hort

-/ int e rm ed iat e- t e rm occ upati ona l dermal/inhalation exposures . The acute neurotoxicity sc r ee ning batt e ry (NOAEL 

## = 250 mg/kg/ day) was se lected for assessment of acute dietary (all popu lat ions ex clud i ng females 1 3 -49 years old) exposure. Th e chronic toxicity (dog) study was se lec ted for assessme nt of c hronic di e t ary ex po s ure (NOAEL = 5 mg/kg/ day). For a ll expo s ur e sce n ari os, a lOOx uncertainty factor (UF) was app li ed ( lOx interspec ie s extrap o lat ion ; l Ox for intraspecies variatio n ; I x FQPA SF (w hen a pplicabl e)). 

### D i e ta ry R is k Est ima tes (Foo d + Drin king W at

e r): Ac ut e and c hroni c aggrega t e di etary (food and drinki ng wate r) exposure and ri sk assess ments were conducte d u s in g th e Di e t ary Ex posure Eva luation Model

- Food Co nsumption I ntake Datab ase ( D EEM-F CID , ve r. 3. 16 ) w hich incorporates the foo d consu mpti on d ata from the U nit e d S t ate s Department of Agr icu lture (US D A) Nat iona l H ea lth and Nutr i tio n Exa mination S urvey , What We Ea t i n America (N HA N ES / WWE IA ; 2003

- 2008). Th e acute and c hronic ana lyses assumed tolerance-level residues o r toleranc e -level res idue s adjusted to accou nt fo r the res idue s of co ncern ( ROC) for ri s k a s sessme n t , 1 00% crop treated , a nd modeled drinking water est im ates
. S in ce adequa te processi n g s tudies h ave been s ubmitt ed whic h i ndi cat e th at tol e ranc es for res idue s i n/on app le j ui ce , g rape ju ice , dried prunes , a nd t o mato puree a r e unn ecessary and s inc e t o leran ces for re s idu es in/o n raisins an d tomato paste are established , the D EEM (ve r. 7.81) default proce ss ing fac to rs fo r th ese co mmod iti es we re re duc ed to 1. The DEEM (ve r. 7.81) d efau lt pr ocess i ng factors we re r e t a in ed for the remaining relevant co mm od iti e s . Th e resulting acute**39%** acute p op ula ti o n-adj u s ted dose (aPAD) ; females 13-49 yea rs oc c upie d the h ig hes t % of the aPAD) and c hron ic**(~96%** chron ic population-adjusted dose (cP AD) ; c hildren ( 1-2 yea rs o ld) had the hi ghest expos ure) dietary risk estimat es are not of conce rn to H E D
. Page 3 of 3 IFlutriafol Human Health Risk Assessment 0422451 

### R es ide ntia l (No n-Occ u pat i ona l ) Expos u re a n d R isk Assessme11t : There are no residential uses proposed or current ly regi s tered for flutriafol. Therefore, re s idential handler and post-application exposure/ risk were not assessed. 

### Aggrega te- R is k Es timates: I n accordance with FQPA , HED mu s t cons ider and aggregate pesticide expos u res and risks from three major so urc es : food, dr inking water, and residential exposures. Because there are no use s for tlutriafol that result in residential (non-occupational) ex po s ure s, the aggregat e assessment need only consider food and dr inking water. Since the d ietary exposure analysis included both food and drinking wate r , the di scuss io n and exposure estimates p resented in the dietary section repre se nt aggregate acute and chron ic exposure to tlutriafol and tho se metabolit es identified as being toxicologically identical to flutriafo l. All aggregate flutri afo l risk estimates are not of concern to 

### HEO. Application of flutriafol also res ults in exposure to T (1,2,4-triazole), TA (triazo lyl alanine), T AA (tri azo l y laceti c acid) , and TLA (triazole lactic acid). These compounds are considered to be toxicolo g ically different from flutriafol. 

### HE D conducted an aggregate ri sk assessment fo r these compounds w ith the resulting exposu re estimates les s than HED 's leve l of concern (LOC ; D426493, 

### T. Morton, 9-Apr-20 1 5). 

### O ccu patio n a l E xp os ur e an d Ri s k Assessme11 t: Based on the proposed use pattern , it h as be en det e rmined that the potential exposure scenarios are s hort

- and i nt e rmediate-term handler and postapplication occupational expos ure s . A new occupational handler assessment was n ot conducted since th e antic i pated expos ure sce nario s (m ixin g/loading and applying via aerial and airblast equipment), maximum application rate (0. 114 lb ai/A) , and recommended level of personalprotec tiv e equipment (PPE) ha ve been assessed previously (04 1 6213 , K. Lowe , 24-Jan-2014). Th e combined occupational d e rmal plu s inhalation handler exposure and ri sk estimates we re not of concern in tho se assessments (i.e. , margin of exposure**(MOE)~** I 00) at baseline and with the u se of gloves, as is required on the proposed label. A post-application occupational assessment has been conducted since there are unique worker act ivities related to hop s, which hav e not been previously assessed. The resulting occupational post-applicat ion dermal exposure and risk estimates are n ot of concern o n the day of application (MOEs = 510-4 , 200). Since th e post-application assessment is not a concern on Day 0 ( 1 2 hours following app l ication) , the restricted-entry interva l (REI) is based on the acute toxicity of tlutriafol technical material. Flutriafo l ha s l ow acute tox icity via the ora l , derma l and inhalation rout es (Toxicity Categories III and IV), i s minimall y irritatin g to the eyes ( Toxicity Category IlI ), and is not a dermal irritant (Toxicity Category IV). F l utriafo l was not s hown to b e a sk in se n sitizer when te s ted in g u inea pigs (Buehler method). Therefore, the acute toxicity categories for this chemical require a 12-hour REI under 40 CFR 156.208 (c) (2) ( iii). The 1 2 -hou r RE I , which currently appears on the propo sed lab e l , i s adequa te for the proposed use. B ase d on the Agency's current practices, a quantitative non-cancer occupational post
- application inhalat ion exposure assessment was not p e rformed for flutr iafol at this t i me. [f new policies or p roce dur es are put into place , the Agency may revisit the need for a quantitative occupational postapp licat ion inhalation expos ure assessment for flutriafo l. 

### E n vir on mental Ju s tice Co n s id era tions: Potential areas of e nvironm e ntal ju stice conce rns , to the extent po ss ibl e, were considered in th i s human health risk assessment , in accordance with U.S. Executive Order 12898 , · 'Fe dera l Actions to Address Environmental Ju s tice in Minority Population s and Low-Income Populations." Page 4 of3 IFlutri afol Human H ealth Ri sk Assessment 042245 1


### R ev i e w of Huma11 R esea rch : T hi s ri s k assess ment r e li es in part on data fro m stud ies in wh ich adu lt human s u bjects we re intent io nall y exposed to a pesticide o r other chemical. These data, which include st udie s from the Pesticide Hand l ers Exposure Databa se (PH E D) 1
. 1 , the Agricu ltura l H andler Exposure Task F orce (A HETF ) database, and th e Agricultu ral Reentry T ask Force (ARTF) database are (1) s u bject to ethics review pursuant to 40 CFR 2 6 , (2) ha ve received that rev iew, and (3) a re co mpli a nt w ith appli cab le ethi cs re quirement s. Fo r ce rtain s tudie s, th e eth ics review m ay have included rev iew by the Hum an St udi es R eview Board. D escriptions of data sources, as we ll as guidance on their use, can be fo und at the fo ll owi n g Age ncy websites: http ://www.e pa. gov/ p es ticid es/sc ienc e/handl er - ex po s ure-d a t a. ht m l a nd http: //v.'WW.epa.gov/ p es ti cides/ sc ience/ post
- app-exposure -d a ta. html
. 2.0 Recomm e nd at ion s Provided the peti tioner s ubmit s a revi se d Secti o n B , HED co ncl ud es th at th e toxico logica l , res id ue chemistry, and occ up at ional/res id ential exposu re databases support th e es t ablis hm e nt of the pe r man e nt to l e ran ce li ste d in Sect ion 2.2
. 2. The most recen t tl utri afo l ri sk assess me nt reco mm e nd ed for the estab li s hm e nt of cotton to lerances in 180
. 629(a) and the del e tion of the cotto n to leranc es in l 80 .62 9 (d) ( 0 415849, T. B loem, l 6-Dec2014). The cotto n tolerances were established in 180.629(a) but they wer e no t dele t ed fo rm l 80.629(d). HED requ est that the cotton tol era nc es from 180.629(d ) be d e l e te d. 2.1 D a ta Deficiencies/ Dat a Nee d s 

### R es idu e C h e mi s tr y : The fo ll owing field rotatio nal crop residue data co ndu cte d as spec ifi ed in OPPTS 860. 1900 are req ues ted ( tri als s hould e mploy a seasonal rat e of 0. 228 lb a i /ac re ): swee t corn - Nort h American F ree T rade Agree me nt (NAFTA) Growing Zo ne s 1 ( n =2), 3 ( n =l). 10 (n = l ), 11 (n = l ), an d 12 ( n = l ). These data were previously requ ested an d remain o u tstan ding ( 0 397075, T. Blo e m , 20- Dec- 20 11 ). The add i ti o nal data we re requeste d to e n sure th at th e resulting ro t at iona l crop tolerances are reflective of cond iti o n s for growers in all re levant r egions. Based on the existing swee t corn and co tto n fie ld rota ti o n al c r o p res idu e dat a ( res idues :50.03 5 ppm) and th e unre fin ed n a ture of the c urre nt d ie tary expos ure an a l yses , H E D concludes that the requested data will not have a significant effect on the human health risk assessmen t. I n addition, the ruminant feeding study monitored fo r residues of only flutr iafol , with the ROC fo r risk assess me nt estimated using factors derived from the ruminant m e tabo li s m stu d y. The factors range from 2

- 77 x and r efle ct th e fact th at parent wa s not th e major res idue in so me of th e matric es. I n orde r to facilitate refinements in t h e d ietary exposure analysis which may be n ecessary as part of fut ure reg i strat io n s, H E D advises the petitio ne r to ana lyze the ruminant feed in g st ud y sa mp les fo r some o r a ll of the ROC for risk assessmen t (storage stabil it y d ata wi ll also b e req uired). HE D notes that the ruminant residue estim a tes employe d in the dietary ana lyses are conservative as they are comparable to , o r s ig n i ficantl y hi g he r than , th e to tal radi oac tive res idu es (TRRs) from th e metabolism study (30

- ppm die tary burde n ) and due to the co n servat i ve n ature of the d ie t ary burden calcu lati ons.

Page 5 of3 IFlutriafol Human Health Risk Assessment 042 245 1 

### 2.2 T oler a nce Co n si dera tion s 2 .2 .1 E nforc eme nt Analytica l Method 

### Tolerance £ 11/ orcemen t Method

- Pla 11t s: Adequate methods are available to enforce the currentl y estab li shed pla n t tolerances (D362421 , T. B loem , l l-Mar- 2009; 03405 1 3, T. B loem, 1 l-Mar -2009 ; 0388603 , T. Bloem, 16-Jun-2011). The tlutriafol method emp loyed in the magnitude of the resid ues stu di es is based on th e current to le ranc e enforcement me thod. Si nc e adequate method va li dation data were provided as part of the magnitude of the residue stu die s , HED conc l udes that the c urr e nt tol e ranc e enfo rcem e nt m ethod i s adequate to enforce the tol erances associated wit h this petition. In add i tion , the QuEChERS method has been shown to adequately quantify re s idues of flutriafol (http: //www.crl-pestic id es.eu/li brary / docs /fv /C RLFV Multiresidue method s.pdt). 

### Tolera n ce E nf orcement M e thod

- L i vestock: Method ICIA AM00306 (rev i s ion s of 1 3-Aug-2007 and 8-0ct-2007) has been determined to be sufficient for enforcement of the curre ntl y established ruminant tolerance s (D36242 l , T. Bloem, 23

- Apr-20 14). The flutr iafol methods em plo yed in the ruminant (49059703.der) and poultry ( 47510201.derl) magnitude of the residue studies are based on thi s m et hod. Since adequate method va li dation data were prov ided as part of these studie s, H ED concludes that the current tolerance enforcement method is adequate to enforce the tolerances associated with th i s petition. 

### 2.2.2 Recommended Tolerance s Table 2.2.2.1 i s a summa r y of the propos ed and HED-recornmend ed tolerance for res idu es of flutriafol per se (proposed tolerance i s appropriate).
T a bl e 2.2.2.1: To l era n ce S umma ry. Co mmodity 

## I Propo se d Tol era nce (ppm) 

## I HED-Rccommcnded To l erance**(ppm~** Co mments 40 CF R 180.629(a) hop
. dried co ne s 

# I 20 

## I 20 

## I

-- 2.2 .3 R ev ision s to Petitioned-For Tolerance s None 

### 2.2.4 Intern at ional Harmonization Th ere are no Cana di a n , Codex , o r Mex i can maximwn residue limits (MRLs) in/on the proposed commodities; therefore, tolerance harmonization i s not an is s ue for this petition. 

### 2 .3 Lab e l Recommendations A revised Section B is requested which indicates that fo ll owing app li cat ion to hop s, the treated field may on ly be rotated to a labe led crop.

Page 6 of3 lFlutriafol Hu man H ea lth Ri s k Asse ss ment 0422451 

### 3.0 I ngred i e n t P r o fil e 3.1 Chemica l I de n tity The chem ical s tructure and nom e nclature of flutriafol and the triaz ole metabolite s are pre se nted in Tables 3.1.1. The phy s iochemical proper ti es for flutriafol a re l i sted in Appendix C
. Table 3. 1.1 : F l ut r iafol Nome n cl a tur e. N

### (~ N

- N F C h e mi ca l s tru c ture 

### I**~**h0 11 

### I**~**hF Co mmon name Flutriafol Co mpan y ex p e rimenta l name PP450 ( I C l/Syngenta until 200 I); C HA 1 3 1 0 -05 (Che min ova code) I U PAC name ( R S)

- 2.4 · -dinu oro -a- ( I //-1.2.4-t ri azo l-1- y lmeth yl) benzhydryl alcohol CAS name (±)

- a-(2-nuoroohenvl)-a-( 4-0u o ro oh e n v l -1 H-1.2.4-tri azo lc- I -ethanol CAS rc iz i s tl) 1 number 76674-21-0 NH,**N~** 0**N~ N~** 

# ~I I N HO**N~N**

## ~~ /,N HN---$ HO -.....§ 1. 2 .4-tria zo l c (T) 0 triazol y lacetic Acid (TAA) tri azo l y lalanin e (TA) 

### 3. 2 Propo se d Use Pattern C heminova requeste d Section 3 R egistratio n s for application of flutriafol to hops. Table 3.2 .1 i s a s ummary of the e nd-u se product and target pests and Table 3.2.2 i s a s umm ary of the proposed application sce nari o . Provided a revised Section B i s submitted which indicates that following application to hop s, the treated fi e ld may on ly be rotated to a labe led crop , H E D co nclu de s that th e proposed app li cat ion scenar i o is supported b y the available residue chem i s try data.
Table 3.2. 1 : S um m ary of End-Use Products. Trade Na me Co ne. Formulation Label Dat e Target C rop s Target Pests Top g uard ® Fung ici de 1 .04 lb ai /ga l s u spens i on not indicated hop s P owdery mildew (Podospltaera (E PA Reg. No. 67760-75) concen trate (SC) 111 ac11laris. Spltaero tli eca macularis) Table 3.2.2: S ummary o f Proposed H o p A pp l icati on Scena ri o. Ap plication Single App. Ma x.# App
. Max. Seasona l P ill Type. Formulation Rate per Season App. R ate (days) Use Dir ect ion s and Li mitation s (lb ai/ acre) ( lb ai/acre) -14-day rctre atmcnt interval ( RTI) -min imum ground and aeria l s pray vo lum es of 30 and I 0 GPA. respectively

- application via ch e mi ga tion is prohibited

- REI = 1 2 hours broadcast SC 0.081-0.114 4 0.455 7**-PP ~**  listed o n th e proposed labe l include s l o n g-s le eved fo liar s pray ( 1 .0 4 lb ai/ga l) shirt and l ong pants. chemica l-resistan t g love s. a nd s h oes p lu s soc ks -adju vam s may be in cl uded in the s pra y s oluti o n -rot a tion to a labeled c rop i s permitted at any tim e: rotati on to cotton/swee t com is permitted 18 0 days after appli ca tion : rotation t o any o th e r crop is prohi b ited

Page 7 of3 IFlutriafol Human H ealth Risk Asse s sment 0422451 

### 3.3 A ntici pate d Expos ur e Pa th ways Based on the propo sed / registered flutriafol application scenarios, dietary exposure is an anticipated exposure pathway as residu es of flutriafol may be found in/on crops , live s tock , and drinking water. Ex po s ure in the resi d e ntial (non-occupational) settin g is not anticipated. Based on the registered/proposed application scenario s and the results of a fish bioaccumulation s tud y , re s idu es in fi s h/shellfi s h are expected to be insignificant (0425447, T. Bloem , l-Sep-201 5; this include s cons umpti on at the subs i stence level). The current action is expected to result in short- and int e rm e diate- term occupational expo s ure s ( hand l er and post
- application). 3.4 Co ns i derat i on of Env i ron m e nta l J ust i ce Potential areas of environmental ju s tice concerns, to the exte nt po ss ible , were considered in this human health ri sk assessment, in accordance w ith U.S. Executive Order 12898 , "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Population s , " (http: // epa.gov/ comp lian ce/ ej / resources/ policy / exec order 12898.pdf). As a part of every pesticide risk assessment, OPP cons id ers a large variety of consumer subgroups according to we ll

- es tabli s hed proc ed ures . In line with OPP policy, HED estimates risks to population s ubgrou p s from pesticide exposures that are based on panems of that subgroup's food and water consumption, and activities in and around the home that involv e pesticide u se in a r es id e ntial sett in g. E xtensive data o n food consumption p attern s are compi l ed by the US DA 's N HANES / WW E IA , are u sed in pesticid e risk assessments for all r egis tered food u ses of a pesticide. These data are analyzed and categorized by s ub grou p s based on age , season of the year, ethnic group, and reg ion of the country. Additionally, OPP i s able to assess dietary expos ure to smaller, spec ialized s ub groups and exposure assessmen t s are performed when conditio n s or circumstances warrant. Whenever appropriate, non-dietary exposures ba sed on home use of pe sticide product s and assoc iated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are eva lu ated. Further considerations are current ly in development as OPP has committed resources and expert ise to the development of specialized software and models that consider expos ur e to by s tanders and farm workers as well as lif esty le and traditional dietary patterns among s pecific subgroups
.

Pag e 8 of3 lFlutriafol Hum an Hea lth Ri sk Assessment D422451 

### 4.0 Hazard C haracterization and Dose-Respon se Assessment Flutriafo l is a m e mb e r of the conazole tr iazo le class of pesticides. The tria zo le fun gic id es inhi bit C 14-dem e thyla se , a fungal cytochrome P4 50, whi c h pl ays a ro l e in s terol production. Stero ls, s u c h as e rgos terol , are nee ded for fungal membran e s tructur e and function , and are essent ial for the development of functiona l cell walls. Mammals , parti c ul arly humans , a l so ex pre ss cytochrome P4 50 e n zy m es ( he pa ti c an d extra-hepatic)
. Thu s , expos ure to c he mi cal s s u c h as flutriafol in suffic ient quantities may lead to tox i c ity. 

### 4.1 Tox icolo gy Studies Ava ilable for Ana lys is The hazard**ata~ase** for flutriafol i s complete a nd a de quate for dose-respon se and FQ P A eva luati o n. Flutriafol was eva lu ated for the fo ll owing: 

### (1) S ub c hronic and chronic o ra l toxicit y in r ats , mic e and do gs; (2) Deve lopmental toxic i ty in rats and rabb it s ; (3) Reproductiv e a nd po s tn ata l toxicity in ra t s; (4) Carcinoge n icity in mice and rats; (5) Ne urotox icity in rats; (6) lmmun otoxic ity in mice ; a nd (7) Gene tic toxicology s tudies. No new to x icit y and/or m e t abolism dat a have been rece ived s ince the last flutriafol ri s k assessment (0420442 , T. B loe m 

### et al. , 16-D ec-20 14 ). It is noted th at HE D 's Hazard and Science P o li cy Committee (HAS POC ) eva luat ed all ex i s ting hazard and ex po s ure dat a, as we ll as c urrent registered use patt e rns fo r :flutriafol, and conc lud ed u si ng a weight

- of-ev id e n ce approach th at a subchronic inhal a tion t oxicity stu dy was not req u i red at that time ( TXR # 0056856)
. S in ce the ap plicati o n scenario proposed for hop s is sim ilar to that eva luated by HAS PO C , H E D co nclud es that a s ub c hro nic inh a lati o n t oxic it y st ud y wo uld not b e required for evaluation of occupatio n a l exposure re s ulting fro m application to hops. 

### 4.2 Abso rpti on, Di stribution , Metabolism , & 

### E limination (ADME) Flutriafol i s quickly ab so rb e d , extens i vely m etabo li zed, and quickly e limin a ted (w ithin 48 ho urs) regardle ss of sex , dose , or w heth e r exposu re was to sing le or multiple dosi ng regim e n s. More than 78% of the dos e was recovered in the bi le and urine. ln th e b lood, rad ioacti vity partitioned into th e r ed blood ce ll s. I n both sexes a nd a ll gro up s , co ncentra tion s of rad ioactiv i ty were hi g hest in who le blood, liv e r , and kidneys. The total amount of radioact ivity isolated in the ti ss ues and carcass was < 1- 3%. B ioacc umul atio n was cons id e r e d unlik e ly. T h e pare nt was i s o l a ted in only trac e a mount s in the ur in e and feces and more than 19 metabolites were i solated , indicating ex tens ive metabo l ism. The primary s ite for metabo li sm was the 2 -flu oro ph enyl ring. The init ia l metabolic step was e poxidation fo ll owe d b y rearrangem e nt to fo rm e ith e r th e dihydrodio l isomers or the hydroxy o r dihydroxy metabolites. Th e h ydroxy l groups on th ese primary metabo lit es may the n be e ith e r conjugated with g lu c uroni c acid o r methy lated. A seco nd , min o r route fo r m etab o li s m of flutri afo l was v i a the remova l o f th e triazo le rin g to form 1

- (2 fluoroph e ny l)- 1 -( 4-fluorophenyl)- ethand io l , w hi ch i s then conjugated w i th g lucuronic acid.

P

age 9 of3 lFlutriafol Human H ea lth Ri sk A ssessme nt 0422451 

### 4.2.1 Dermal Absorption An 

### in v ivo rat derm a l-ab so rpti o n s tud y (MRJD # 4 7090415 ) i s available for flutriafol that i s acceptab le and indicates that the absorption i s 17 %, 21 %, and 11 %, res p ecti ve l y, at 2, 20 , and 2 00 μ g/c m 2
, fo llo w ing a 10-h o ur exposure calculated as th e s um of absorbed and potentiall y ab so rbable re s idue s at the s kin s ite . A va lu e of 2 1 % i s appropriat e ( m ost prot e ctiv e) for dermal ri s k assessments. 

### 4.3 Toxicological Effects Consistent with the mamm alian tox ic ity profile s of th e o ther triaz o le fun g ic id es, th e pr eva lent adverse effects following oral exposure to tlutriafol we r e in th e li ver. Effe ct s co n s i sted of; inc re ases in li ve r enzyme re le ase (a lkalin e phosphatase) , li ve r wei g hts . and hi stopatho l ogy findings (hepatocyte vac u o lization to ce ntrilobul ar hypertrophy and slight in creases in he mosid e rin-l ade n Kupffer cells. minimal to seve re fatt y changes, and bile duct proliferation/cholan g iolar fibro s i s . Pro g ression of toxicity occ urre d with tim e as so me effects were onl y observed at chro nic d urati o n s. These e ffect s w ere cons i s tent with the ADME data in term s of the amount of do se ab s orbed and bio transformed , a nd the ti ssues whe re the ch e mical was mo st s ignificantl y de tected. S li g ht indi cations of effects in the hematopoietic sys t e m we re sporadically see n in a ll s pe c ie s consisti n g of; s li g ht anem ia , increased platelets , whit e blood ce ll s, neutrophil s, and lymphocytes. T he effects in the n e uroto x icity sc r eening batteries were observed on l y at hi g her d oses and were cons idered secondary effects (decreased motor activity and hindlimb g rip st r e ngth , ptosi s , lo s t ri g htin g reflex , hunche d posture, and atax ia). Flutriafol s h owe d no evidence of d e rmal toxicity , or imrnunoto x icity. Fl utri afo l s ho wed no ev iden ce of carc ino ge ni c ity in rod e nts o r 

### in vitro
. T he re i s ev id e nce of increase d quantitative and qualitative pre- and postnatal s usceptib il ity for flutriafol in rats and rabbit s. In the first of two rat de ve l opmental toxicity studies , developmental effects ( delayed ossification or non-o ss ification of the ske leto n 

### in the fetuses) wer e obse rv ed a t a lowe r do se than that where mat erna l effec t s were observed. In th e seco nd r at de ve lo pm e ntal study, d eve lop m e nta l effects (ex t e rn a l , visc e ral , and ske leta l malformations ; e mbryo leth a l ity ; s k e letal variati o ns ; a g en era li zed del ay in fetal d eve l op ment ; and fewe r live fe tus es) were m o re severe than the decre a se d food co n s umpti o n and body-weight gains ob se rved in th e darn s at th e same do se. For rabbits, intraute rine death s occurred a t a d ose level that a l so c aus e d adverse effects in mat e rna l a nima ls. Jn the two-generation reproduction s tudie s , effect s in th e off s pring [d ec rea sed litt e r size and perc e ntag e of li ve birth s ( increased pup morta lity) and li ver to x icity] can be attr ibute d to the systemi c toxicity of the pa re ntal animals (decreased bod y we ig ht and food consumptio n a nd liv e r toxicity ) o bserv e d at the s ame dose. F l utriafol i s ca tegorized as ha v ing hi g h ora l acute toxicity in the m o u se ( To x ic i ty Category IT ). It is catego rized as h avi n g l ow acute toxicity via the ora l , dermal and inh a lation rout es (Tox icity Catego ri es III , III , and IV , respectively) in rat s. F lutri a fol i s minimall y irrita ting to th e eyes (Toxicity Category III) and i s not a d e 1mal irritant (Toxicity Category 

### TV ). F lutri afol was not s hown to be a ski n se n s iti z er when tested in g uin ea pi gs ( Bu e hler method)
.

Page 10 of3 IFlutriafol Human H eal th Ri s k Asse ss ment 04224 5 1 4.4 Safety Factor for Infants and Children (FQPA SF) T h e RABI risk assessment team concluded that th e FQPA SF could b e reduc e d to Ix ba se d on the fo ll owi n g co n s iderations outlin ed in m o re detail in the sec ti ons be lo w : 1) th e toxicology databa se for flutriafol i s adequate for ri sk assess ment ; 2) flutriafol i s not co nsid e r e d ne uroto x ic ; 3) clear N OA ELs ar e es tabli s hed to prot ec t for the fetal/off s pring e ffect s obse rve d and se lected e ndpoin ts are protecti ve of th ese effects; and 4) the exposure d atab ases ar e suffic i e nt a nd unlik e l y to undere s timate ex p os ure . 4.4.1 Completeness of the Toxicology Database T he toxicology d ata ba se fo r flutriafol i s adequate for quantification of ri s k for dietar y, res idential , a nd occupationa l u ses and FQP A SF eva lu ation. T he fo ll ow ing acceptab le s tudie s a re ava ilabl e for eva lu at io n: d eve lopmenta l toxicity studi es in rat s (2) and rabbits ( I) , two - ge ne rat ion reprodu c tion s tudi es in rat s (2) , a nd ac ut e and s ub c hro ni c neurotoxic ity s tudie s in ra t s . 4.4.2 Ev idence of Neurotoxicity T here i s no co n cern for n e uroto x ic it y with tlutriafol. Signs of ne urot ox ic ity were r e ported in the acute and s ubchronic n eu rotoxicity studies at th e hi g hest do se o nl y; howeve r, these e ffect s were primari ly see n in animal s that were agonal (a t the point o f d e ath ) and , thus , are not indicative of neurotoxic i ty. In a dditi on , there was n o evidence of neurotoxicity in any additional s h o rt
- t erm or lo n g -t e rm toxicity s tudi es in rat s, mice , and d ogs . 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal There are no conce rn s or r es idu al unc e rt ai nti es for pre- and/ o r post -nata l toxicity. T here i s ev id ence of increased quan titati ve and qu alitat i ve suscept ibili ty in dev e lopm e ntal and rep ro ducti o n toxicity s tudi es (see Sec tion 4.2) ; however , there conce rn i s low s ince: 

### 1) clear NOAELs and lowest o bs e r ve d adverse e ff ec t le vel s (LOAELs) were established for e ffect s in th e fet u ses/ offs prin g; 2) the dose -re s p onse for th ese effects a re we ll define d and c haracterized ; 3) d eve lopmental e ndpoint s are u se d for assess in g acute di e t ary ri s k s to th e mo st s en s itiv e populat io n (fema les 13-49) a s we ll as all o th er s ho rt
- and interme dia te-term expos ure scenarios ; 4) th e acute r e ferenc e do se fo r fe mal es 13-49 i s 1000-fold l owe r than the do se at which quantit a tive sus ceptibilit y in the first developmen t a l rat stu dy was ob serve d ; an d 5) the chro ni c reference do se i s g reater than 3 00-fo ld lower than th e dose s a t which the offspr in g effects we re ob se rved in the two-generat io n repro du cti o n s tudi es . 4.4.4 Residual Uncertainty in the Exposure Database The re a re no residual un ce rtainti es in th e exposure datab ase. Th e dieta ry exposure assess me n t i s co ns e rvative in nature (utilizes toleranc e -l evel res id ues and 1 00% crop treat e d). In additio n , th e re a r

e no propo se d or reg i s t ered resident ia l u ses.

Page 11 of3 IFlurriafol Human Health Risk Assessment 0422451 

### 4.S Toxic i ty E ndpoint and Point of D e parture Se lections 4.5.1 Do se-Res ponse Assessment The POD s , UFs, and toxicity endpoints for d ietary exposure assessme n t and occupational exposure assessment are presented in Tables 4.4.1 and 4.4.2, respectively. 

### Acute Die tary Endpoint (General Population): The acute neurotoxicity screening battery in the rat was se lected for the acute dietary endp oi nt for the genera l population. A total U F of lO Ox ( lOx for interspec ies extrapolation, I Ox for intra.species variab ilit y, and 1 x for FQPA SF) was applied to the NOAEL of250 mg/kg to gene rat e the ac ute reference dose (a.PAD) of2.5 mg/kg for the general popu lation. The LOAEL is 750 m g/kg based on decreased body we ight, body-weight gain. absolute and relative food consumption, agonal effects in both sexes (dehydration, urine-stained abdominal fur, ungroomed coat , ptosis, d ec reased motor activity, prostration , limp muscle tone , muscle flaccidit y, hy poth e rmi a , hun c hed posture, impaired or lo s t righting reflex, a nd scant feces), in ma les (red o r tan perioral substance, chromodacryorrhea , chromorhinorrhea, labo red breathing, and s li g ht ataxia), and in females (piloerect ion and bradypnea)
. This study is protec ti ve of the general population and i s appropriate for the expected duration of exposure. 

### Ac ut e R eference Di e ta ry Endpoint (Females 1 3 -49 years o ld): The rabbit prenatal deve lopmental toxicity s tudy was se lected for the acute di e tary e ndp oint for females 1 3-49 years of age. A total U F of lOOx (!Ox for interspecies extrapolation, ! Ox for intra.species variabi lity, and lx for FQPA SF) was applied to the d eve lopmental NOAEL of7.5 mg/kg to generate the a.PAD of 0
. 075 m g/kg for fe mal es 13-49 years of age. The developmental LOAEL of 15 mg/kg i s based on d ecreased numb e r of liv e fet u ses, complete litter resorption s, and increased post-implantation los s. Th e NOAEL selec ted provides the lowest NOAEL from any toxicity study in the flutriafol database in which a toxic re sponse could be the outcome of 1 -2 days of s ingl e dosin g . The o nl y other studies considered for this endpoi nt we re the prenatal developmental studies in rats, where the d eve lopmenta l NOAELs were I 0 m g/kg in both stu di es with dev e lopme ntal LOAELs of 50 mg/kg/ day ( 1982) and 75 mg/ kg/ day (2008). The rabbit study i s therefore protective of the effec t s see n in these rat studies and provides the mo s t protective endpoint for the population of concern (pregnant females and fetuses). 

### Chronic Dietar y E 11dpoi11t (All populatio11 s): The chronic dog toxicity study was selected for the chronic dietary e ndpoint for the genera l population. A total UF of 1OO x (1 Ox for inter species extrapolation , l Ox for intraspecies variability, and lx for FQPA SF) was applied to the NOAE L of 5 m g/kg/day to ge nerate the chronic reference do se (cPA D) of 0.05 m g/kg/ day for all populations. Th e LO AEL i s 20 mg/kg/day based upon adverse liver findings ( i ncreased li ver we ights, increased centrilobular he patocyte lip id in the li ver, a nd increa ses in alkaline phosphatase, a lbumin , and triglycerides) , increased adrenal cortical vacuo li zation of the zona fasciculata, and mark ed hemosid e rin pigmentation in th e li ver and sp leen in both sexes, mild anemia (characterized by decreased hemoglobin, hematocrit , and r ed blood cell coun t) in the males , a nd initi a l body-weight lo sses, decreased cumu l ative body-we ight ga in s, and increa se d adrena l weights in the fema les. T hi s NOAEL is protective of all effects seen following chronic exposure to flutria fol. In a dditi on , the s tud y duration i s appropriate for the duration of exposure. Both th e 28-day rat a nd 90-day dog ora l toxicity studies provide s imilar NOAEL/LOAE L values and toxic effects (adverse liver effects) as th e chro ni c do g s tud y. Oth e r s tudie s considered for this endpo in t we re the chronic /carcinogenic ity studies (mouse and rat) , as well as the two-generation reproduction studies where s im ilar effects were seen at s li g htly high e r do ses . Pagel2of31f lu triafo l Hum an H ea lth R isk Assessme n t 042245 1 Sltort- and /11term e diat e -Term Dermal and J11/talatio11 E11dpoi11t: T he rabb it pre n at a l deve lo pm e n ta l tox ic ity stud y was s el ec ted fo r the s ho rt
- and in te rm e di ate- te rm dermal and inhalatio n end p o ints. The develo pme nta l NOAE L i s 7.5 mg/ kg/ d ay an d the LO AEL is 1 5 mg/ kg/d ay, ba se d o n d ec rease d numb e r ofl ive fet u ses, c o mpl e te li tte r r eso rp tion s a nd in c rease d pos t-im p la nt a ti o n loss. A ltho ug h m a t e rnal and deve lo pm e nta l toxici ty were obse rv ed a t the s am e dose , the mate rn a l effects were r estricted to mo de rate dec reases i n body weig h t an d food co n s ump tio n , and we r e less seve r e than th e effec t s obse rve d in th e offs p ri n g . In ad diti on, a lth o u g h decreased bo d y weig h t was an adve rse effect observed in non- pregnant ani m als wi th fl utr iafo l , results of th is stu dy in d ica te th at preg n ant anim a ls we re more se n s iti ve to thi s effec t. Th e rout espec i fic 28- d ay de rm a l tox ic i ty s tud y was a l so co n s ide red for de rm al expos u res, but t h e r e was no toxici ty observe d up to the l im i t dose (I 000 mg/kg/d ay) an d deve lop me n ta l effects were no t eva lu a te d
. Th e se lec te d stud y p rov id es th e most p ro t ec ti ve e ndpoin t fo r th e p o pul a ti o n s of co n ce rn (pregnant femal es an d fe tu ses). O th er stud ies co n s id e red fo r de rm al an d inh a l at ion scenari os we re t he 90

- day dog an d the two - ge n era ti o n re produ ctio n st ud ies (pa re n ta l effec t s) w h e r e li ve r toxic ity (t

h e target org an ) was observe d at s imil a r doses as the rab bi t deve lop menta l s tud y. T he LOC for the derma l and inhalat io n e ndpo i nts is 100 based upon a 1 Ox fo r i nterspec ies ex tra p o lat ion , an d a 1

Ox fo r intras p e ci es v a ri a bilit y. U s in g a de rm a l- a b so rpti o n fac to r of 2 1 %, th e d e nn a l-e qui va le n t NOAEL is

- 35.7 mg/kg/day (NOAE L o f 7.5 mg/ kg/day 

### I 2 1 % dermal absorption = 35.7 mg/kg/ day. Inha la ti o n expos ure i s ass um e d to be e qui va le nt to o ra l ex po s ur e). 

### 4.5.2 Recommendation for Combining Routes of Expo s ure for Risk A s sessment Since the PO D / end p o int for sho rt
- and intermediate-term de r ma l and inha lation e ndpoi nt s are iden t ical, ex p os ure via t h ese ro u tes m ay be co m b ined. 

### 4
. 5
. 3 Cancer C lassification and Ri s k As se ss ment Recommendation Fl ut ri afo l is cl assi ti e d as " n ot lik e ly to be carcinogen ic to h umans" base d o n the res ul ts of the carci noge n icity stud ies in rats and m ice.

Page 13 of3 IFlutriafol Human H ealth Risk Assessment 04 2245 1

Tab le 4.5
. l : Summary of T ox ico logica l Do s es and Endpo in t s for F lu triafol for Use in Dietar y and No nOc c uoationa l Human H ealth Ri s k Assessme n t s .

Exposure / POD Uncertainry/ FQPA RID , PAD. LOC for Study and Toxicological Effec t s Sce nari o SF s Ri sk Assessment Neurotoxicity sc reening battery

- rat: LOAEL 

### =750 m

g/kg, based on decreased body weight. body-weight gain. Acute Dietar y Acute RID = 2.5 absolute mid relative food con s umpt i on. and clinical s i g n s (General NOAE L = U FA= I Ox m g/kg/day of toxicity in bo th s exe s: dehydration. urine- s tained Popul at ion , 250 U Ftt = ! Ox abdomina l fur. ungroomed coat. ptosi s, decreased motor including mg/kg/ day FQPA SF= Ix aPAD 

### =2.5 activity. prostrat ion. limp mu s cle tone. muscle flaccidit y. In fa nt s and hypothermia
. hunched posture, impaired or lo s t righting Child ren ) mg/kg/day reflex. scmi t fece s : in males: red or tan pe ri o ra l s ub s tance. chromodacryorrhea, chromorhinorrhea and labored breat hin 1.t. and in fe ma le s : oiloerection mid bradvonea. Acute Dietary Acute RID = 0.075 Developmental s tudy - rabbit: Developmental LOA EL = (Fema les 1 3- NOAEL = 7.5 UFA = IOx mg/k g/day 15 mg/k g, based on decreased number of live fetuse s . UFtt = IOx 49 ye ars of m g/kg/ day FQ PA SF = I x a PAD = 0.075 complete litter re s orptions and increased post-imp l antation age) ml?./k11 / dav loss. Chronic tox i city

- dog: LOA EL = 20 mg/k g/ day. bas ed on adverse liver findings (increased liver weight s. increased ccnt ril obu l a r hepa tocy te lipid in th e liver. and increas e s in Chronic RID = 0.05 alkaline phosphatase. a lbumin
. and tri g l ycerides). C hronic iNOAE L = 5 UFA= I Ox mg/k g/day increased adrena l cortical vacuolation o f the zo na Dietary (A ll U Ftt = I Ox fasciculata, and marked hemo s iderin pigmentat i on in the Population s) m g/

k

g/da y FQPA SF= I x cPAD = 0.05 liver and s pleen in both s exe s : mild anemia (characterized mg/k g/day by decreased hemog lobin, hematocrit. and red blood ce ll count) in the males: and initial body weight l o ss es, decrease d cumulative bo dy-weight gains. and increased adrena l weight s in th e fe ma l es. Cancer (oral. dermal, Cla ss ification: "'No t lik ely to be C arcinogenic to Human s'' based on th e carcinogenicit y s tudi es in rats and mice. inh a lation ) Point o f dcpanure (P OD ) = A da1a p o int or an csumated point that ts derived fr om observ ed do s<>re spo n se da1a and u sed t o mark the bcgmn111 g of ex trap olation to dctcnninc risk associa t ed wi th lower environ m enta lly relevant hum an exposure s. NOA E L= no-observed adversc.'-effect l evel. LOA EL = J o,1c s t-observed adverse-effect level. UF = unccnainty factor
. UF" = extrapo l ation from anima l t o human (i nte rspecies)
. UFH = potential variation in se ns itivit y among membe rs of the human population (intraspc ci c s)
. FQPA SF = FQPA Safety Factor
. PAD = populationadjusted do se (a= acute , c = chronic)
. RfD = reference do se. Table 4.5 .2: Summary of Tox i col og ica l D oses a n d Endpoint s for Flutr i afol for Use i n Occupational Human He a l t h Ri s k A ssess ments. Exposure/ POD U Fs LO C Ri sk Study and Toxicologica l Effects Scenar i o As sess ment Dermal IN OA E L = 7.5 mg/k g/da y Occupational Developmental toxicit y- rabbit; Developmental Short ( 1-30 days)- 1Dermal-ab s orption factor = UFA = !Ox LOC for LOA EL = 15 mg/k g/day . b ased on decre ased and lntenncdiate ( 1

- 2 1 % UF11 = I Ox MOE < 1 00 number of li ve fetus es, comple t e liller 6 months ) -Tcm1 resorptions and incre ased po s t-implantation lo ss. Inh a l ati on S hort (I- NOA EL = 7.5 mg/k g/day Occ up atio nal Development a l toxic it y - rabbit: Developmental 30 days)- and Inhalation tox icit y assumed to UFA = IOx LO C for LOA EL = 15 mg/k g/day. ba sed on decrease d Intcnnediatc ( 1- 6 be equiva l ent to oral toxicity ' UF11 = I Ox MO E < 100 number of live fetu ses. complete liner months)

- Term resorotions and increase d oo s t-imolantation loss. Cance r (oral. C las s ification : ·· ot likel y to be Ca rcino ge nic to I luman s "" based o n the carcinogenicity s tudie s in rat s and dermal, inhalation) mice
. 1 Dcnnal absorption factor w as denv c d fr om the demial pcnetra1t on s tudy (MRID 47090415): 111hala1ton absorptton factor a s considered the wors t-case scenario for inhalation expo s ure u s ing an ornl NOA F.L (0372 347
. K
. Lowe e t al
.. 1 6-Dcc-2009)
. Point o f departure (POD)= A da1a point or an es timat ed point that is derived from obse rved d oso-rcsponsc da ta and u se d to mark th e beginning of extrapolation to detcnninc risk associated with l ower environmentally relevant human exposures . NOA E L = n o-ob served adver9:-effect level. LOA EL= l owes t-ob served adverse-effect l evel
. U F 3 uncertainty factor
. U F

"**extrap lati** **n** fr om aninrnl t o hum an (interspecie s). U F 11 = potential variation in s ensitivit y an1on g members of the l'l!man p opu l ation (i ntra spcc i es)
. MOE = margin of expo s ure . LO C = levd of concern .

P

age 14 of3 IFlutri afo l Hum a n H ea lth Ri s k A ssess ment 04 2245 1 

### 5
. 0 Di e t ary Ex p os u re a nd Ri s k Assess m e n t 0425446, T
. Bl oem, l-S ep-20 15 ( r es idue c h e mi stry) ; 04 2544 7 , T. Bloem , 1-S e p-2014 (d i et ary expos ure) 

### 5
. 1 Meta b o lit e/Deg r ad ate R es id u e P ro fil e Ba se d o n th e ava i lable apple , s ugar be e t , rape seed , poultr y, and ruminant me tabo l i s m studies and the confined rotational c rop s tudie s, HED con c lude s that th e re s idue of concern fo r tol e ran ce enforcement , in the proposed/re g i s te red primary crops, rotational cro ps , an d li vestock, i s flutriafol. The ROC for risk assess me nt are defined in Table 5. 1 .1. De fluorinated flutri afo l (s ing le flu o r i ne was re moved ) was identified in th e canola metabolism study ( p o d without the see d - 12 -15% TRR (S 0.12 ppm ); seed - 3% TRR ( S 0.04 ppm)) indi cating that fl u tr iafo l may contri but e to fluo rid e d ietary exp o s ur e . HE D ha s previous ly conducted dietary expos ure anal yses for flu o rid e res idue s from th e insectic id es cryo lit e and s ulfury l fluoride u ses as well as from n aturall y occ urrin g fluorid e residu es in food a nd water ( D3855 3 9 , M. Doh e rty , 7- Jan- 20 1 1 ). For the fo ll owing reaso n s, HED conc lud es that fluor id e expo s ure re s ulting from the appl ication of flutriafol are in s ignificant w hen compare d to exposure es tim ates generated in the D 385539 me mo (revi se d asse ss me nt i s unnec essary) : (1 ) based on the id e nt i ficat ion of deflu o rinat e d flutriafol in on ly the can o la metab o l i s m s tudy , HE D co nclud es that defluorinated tlutri afo l m ay be pr esen t in o nJ y hops, cotto n , soy bean seed , and peanu t ( d e fluorin ated flutri afo l was not identifi ed in th e apple , s ug ar b ee t , rotatio n al crop , and li ves tock me tabo l i s m s tud ies or in the e n v ironm e nta l fate/ de g radation studies); (2) a flourid e r es idu e estimat e of 0.008 ppm can be calcu la t e d u s in g the 0. 1 2 ppm d e tluorin ated flut r iafol re s idue from the cano la me t abolis m s tud y and ass umin g a one to o ne mo la r ratio ( s ingle fluorine was remo ve d ; defluorinated tl utriafo l was not id e ntified in the fate o r rotati o na l crop s s tudi es i ndic a tin g that deflu o rinatio n occurred in the plant ); an d (3) th e flu o rid e dietary expo s ure anal ys es assu me d a flu o rid e res idue of 0.496 ppm in ho p s, cot ton , soy bean se ed , and p e anut a nd 0.1 52 ppm in ce real g r ains
. Ta b l e 5. 1. l : S umm ary of Me t abo l i t e s a n d Del?radatc s o f Co n cern fo r R i s k Asse ss me n t a n d To l e r a n ce E n forceme n t. Matrix RO C 1 Ri s k Asse ss ment To l erance E n forcement coffee. soy bean see d. fruit. s ugar beet. cucurbit vegetables
. fruiting flutriafol (free). T. TA. and TAA vegetable s. tree nut s. a nd leaf y vegetab l es (croo gro uo s 4 and 5) hop s. cotto n . peanut. and cereal flutriafol (free and conjuga ted). defluorinated flutriafol. T. TA. and TAA: gra in s combined nutriafol ( free and conjugated) and dcnuorinated nutriafol r es idu es may be es timat e by multiolving the fre e flulriafo l res idu es b y 2.2x2
ro tatio n a l c ro p s (exc ludin g dried nutri afo l (free and co nju ga te d)
. M28. T. TA ( fr ee and co nju ga ted). TAA , roughage feed commodities) and TLA: combined flutriafol (free and conjugated) and M28 resid ue may nutriafol (free) be es t imated by multiplving the free nutriafol re s idue by I .3x2 rotationa l c ro p s (d ri ed roug h age same as that mentio ned above but with multiplicati o n of th e fr ee nutri afo l res idu es by 2.0x to acco unt for the combi ned re s idu es of flutriafol ( fr ee and feed commod iti es) conj u gated) and**M28 ~**  IPOU1trv 3 nutriafol (free). T. TA. and TAA flutri afo l ( fre e), M 3. M3 c , M4
. M 7 , M I O. T. TA. and TAA: co mbined Ruminant nut ria fo l. M 3. M 3c, M4. M7, and M I 0 re s idues may be es tim ated by multipl y ing the free nutriafol re sidue by lhe followini: ski m milk

- 58x. cream - I Sx, liver. 5.3x. kidne y 77x. mu scle

- 6x. and fat

- 2x Wa ter flutria fo l a nd T 

### -- 1 For information co nc e rnin g th ese conclu s i o n s, se e lh c fo ll owing: 0355605. B. Oais s. 3-Se p- 2008: 0372 347. K. L owe e t al.. 16-Dec-2 009: 0388603. T
. Bl oe m. 16-Jun-2011: 0380493. T. Bl oe m. 16-Jun-2011: 0396758. T. Bloem
. 1 3-Ma r-2 0 1 2: 04 1 6089. T. Bloem. l 6-Dcc-20 14
. Separa te risk assessments arc required for T a nd TAffAAfT L A ( th ese co mpound s h ave been determined to be t ox i co l ogica ll y differen t from flutri afo l )
. 2 The indicated factor s are base d o n re s ult s fr o m the metabo li s m s tudies or con fin ed rotational c rop s tudy. 3 Decision will be reevaluated as the dieiary burden increases.
Pa ge 1 5 of3 IFlutriafol Human H ea lth Risk Assessment 0 42245 1 

### 5.2 Foo d R es idu e Pro fil e The fo ll owi ng paragraphs are s ummaries of the ava il able magnitude of the residue data for the reg i s tered cro p s , proposed crops , rotat i o nal crops, and li ves to ck. 

### Reg is tere d P rima ry Cro p s: Adequate magnin1d e of the re s idue dat a have been s ub m itt ed to support the c urrentl y-estab li s he d tolerances. 

### Magnitu de of til e R es idu e - Ho p s: T h e s ubmitted hop field trial da ta fulfi ll th e da t a r e quire me nts specified in OCSPP 860.1500. The collected s ample s were ana lyzed for res idue s oftlutriafol , T , T A , and T AA u s in g ade quat e ly validated m et hod s (s torage intervals h ave also been va lidat ed)
. No additio n a l field trial data are required. B ased on the Organization for Eco no mi c Co

- o perati o n and D eve lopment (OEC D ) toleranc e-c alculation procedure , HED concl ud es that th e hop tole rance li s ted in Table 2.2 .2. l for res idu es of flutriafol per se is appropriate. 

### Mag n itude of tlt e R es idu e - R o tati o n al Crops: The proposed lab e l indi cates th at treated fields ma y b e rotated to a la b e led crop at any tim e and to s weet co m and co tton 180 d ays after application ( rotati o n to any o ther c rop is not permitted). In sup p ort of the 180-day pl ant-back interval ( PB I) , th e p etiti o ne r c i ted prev iousl y s ubm i tted and r ev iew e d swee t co rn and cotton field rotational crop data which employe d an app li cat ion rate of 0.228 lb ai / acre (0
. Sx) and resu l ted in the estab li shment of toleran ces for res idu es in/o n sweet com ear / forage / stover and cotton seed/g in byproducts at 0
. 01- 0.09 ppm. Since field rotat ion a l crop data condu cte d at seaso nal ra t es > 0.228 lb a i / acre are not availabl e and ba se d on the proposed seaso n al appli cat ion r ate of 0.455 lb ai / acre, HED concludes th at on ly a labeled crop may be rotated fo ll o w in g app li cati o n to hop s (a re v i se d Sec tion Bis requested). 

### M a g nitu de of tlt e R esidu e - L i vestock : Based on th e OCSPP 860.1000 Table 1 (see feedstuff revis io n of 30-Ju n- 2008) , there are not livestock feedstuffs associ ated with hops. Therefore , a di sc u ss io n concerning th e mag nitud e of th e res idue in livestock i s unn ecessary . 

### 5.3 Dr inkin g Wate r Resi du e P r ofil e Tab le 5.3. l is a summary of worst case flutriafol per se s urface- /ground-water estimated drinkin g water concentrations (E DW Cs) when co n s id er in g all proposed/regi s tered u ses (EFE D ; 0422918 , J. Wolf , 4-Mar-2015). T h e bolded ED W Cs from Table 5.3.1 were incorporated direc tl y in to the dietary ex posure ana l ysis v ia th e water so ur ces direct (all sources) an d in d ir ect (all so urc es) co mmodities . The water mod e ls and their desc ription are available at the E P A int e rnet s ite: http: //www.epa.gov/ oppef ed 1 / models/ water /
. Tab le 5.3. l : Maximum F l utriafo l EDWCs. Model Aoolication Rate Co ncentration (ppb) gro undwater (PRZM-GW') 4 x 0. 11 4 lb s ai/ae re: R T I = 1 4 days acute 1 93 chronic 16 5 su rface water (SWC C 1 ) 4 x 0. 114 lb s ai/ac re: RTI = 14 da ys acute 15 .9 chronic 5.39

.. 1 Pc s 11e1d e R oo t Zone Mode l- Gro undw ate r ( P RZM-GW): FQPA I nd ex Re se rvoir Sc r eenmg Too l ( FIRST vcr. 1 .1. 1 ): Surface Water Concentration Ca l culator (S W CC).

Page 16 of3 IFlutriafol Human H ea lth Ri s k Asse ss ment 0422451 

### 5.4 Di etary (Food+ Drinking Water) Risk A ssess ment The fo llowin g text co ncerns exposure and ri s k to fl utr iafo l and those metabolites identified as being toxicologically the s ame as flutriafol. For information concerning exposure an d ri s k to T a nd 

### T NT AAffLA, which HED has determined to be toxicologica ll y different from flutriafol , s ee the Aggregate Sect ion (7.0). Ac ut e a nd chronic aggregate di etary (food and drin king water) ex po s ur e and risk assessments we re co nducted using D EEM-FC ID (ver. 3. 1 6) w hi ch incorporat es the food consum ption data from US D A NHANES/WWE IA (2003-2008). The acute and chronic analyses assumed tolerance -le ve l residues or tolerance-level res idue s adju s ted to accou nt for th e ROC for ri s k assess ment , 

### J00% cro p treated , and m ode led dr in king wate r estimates. S in ce adequate proce ss ing studies have been submitted which indi cate that tolerances for r esidues inion apple juice, g rape juice , dried prunes , and tomato puree ar e unnecessary and s inc e to lerances for res idue s in/on raisin and tomato paste tolerances are estab li s hed , the DEEM (ve r. 7.81) default processing factors for these commodities were reduced to l
. The DEEM default processing factors we re reta in ed for the remaining re le van t commodities. The re s ultin g acute**39 %**  aPAD ; females 1 3

- 49 years occupied th e high es t % of the aPAD) and chro nic**(~96%** cPAD ; ch i ldren ( l- 2 y ears o ld ) had the hi g hest exposure) dietary risk est im ates are not of concern to HED. Table 5.4 .1 i s a summary of the acute and chronic dietary risk estimates. Table 5.4. 1 : S umm a r y of the Ac ut e a n d Chron i c Di eta r y Ex p os ure a n d Ri sk. Population aPAD Expos ure o/oa PA0 1 c PAD E xposure %c PAO (mg/kg/day) ( m g/k g/ day)' (mg/kg/ d ay) ( m g/kg/day) General U.S

. Population 0.040729 1. 6 0.0 145 70 29 A ll Infant s (< I yea r old) 0 .071406 2.9 0.025073 50 C hildren 1-2 yea r s o ld 0.095739 3.8 0.048076 96 Children 3 -5 years old 2.5 0.08000 1 3.2 0.033853 6 8 C hildren 6-12 yea r s old 0.047907 1.9 0.05 0.0 1 9337 39 Youth 1 3- 1 9 years o ld 0.026897 I. I 0.0 10276 2 1 Adu lts 20-49 years old 0.029368 1.2 0.0 11 790 24 Adults 50-99 yea rs old 0.029925 1. 2 0.0 1 2 109 24 Fe male s 1 3 -4 9 years o ld O.o75 0.029546 39 0.0 114 55 23 1 95•h percentile (tier I analysis).

P age 17 of3 IFlurriafol Human Health Ri sk Assessment 6.0 Residential (Non-Occupational ) Exposure/Risk Characterization There are no residential u ses proposed or currently regist e red for flutriafol. Therefore, res id ent ial handl er and po st
- application exposure/ ri sk were not assessed. 6.1 Spray Drift 0422451

Sp ray drift is a potentia l sou rc e of exposure to those nearby pesticide applications. T his is part i cu larly the case with aeria l application , but , to a lesser extent, sp ray dri ft can a l so be a potential source of exposure from the ground applicat ion methods (e
. g . , groundboom and airb la st) employed for flutriafol. Th e Agency has been working wit h the Spray Drift Ta s k Force (a task force composed of var ious r eg i stra n ts whic h was developed as a res ult of a Data Ca ll

- r n issued b y E PA ), E PA Regional Offices and State Lead Agencies fo r pesticide regulation and other partie s to deve lop the best spray drift management pract ices (see the Agency 's Spray Drift website for mor e information; http: //www.eoa.gov/ opp00001 / factsheets / spraydrift.htm) Th e Agency is a l so taking means to quant it ative ly and qualitative ly address spray dri ft as a potential source of ex po s ure in risk assessments for pesticides through existing programs such as Ag Drift ® and chemi ca l s pecifi c properties of pesticides. Th e potential fo r spray drift w ill b e qua ntitatively evaluated for each pe st icid e during the R egistra tion Review process , which ensures that all u ses for that pesticide w ill be considered concurrently. 

### 6.2 Residential Bystander Po s t-Application Inhal at ion Exposure Volati li za ti on of pesticides may be a source of post-app li cation inhalation exposure to indi vid ual s nearby pes ti cide applicat ions. The Agency sought ex pert adv ice and inpu t on issu es related to vo latilization of pesticide s from its Federal In sec ticide , Fungicide , and Rodenticide Act (FIFRA) Sc ientific Adv i sory Pan e l (SAP ) in December 2009 , and received th e SAP's fi n al repo rt o n March 2 , 20 I 0 (hnp: //www .epa.gov / sc ip o ly/ SAP/mee tin gs/ 2009/120 I 09meeti n g.html)
. The Agency h as eval uated the SAP report and has developed a Volatilization Sc reening Tool and a s ub seq uent Vo lati li zation Scree nin g Analys i s ( h ttp://www.regu lations.gov/# !docketDetail ; D =E PA-HQ-OPP20 1 4-0219). Duri n g Reg istr atio n Review , the Agency will util ize this analysis to determine if data (i.e., flux stu di es, route-specific inh a lation toxico log ical stud i es) or fu r ther analys i s i s req uired fo r specific c hem ical s.

Page 18 of3 lFlutriafol Hum an Health Risk Assessment 0422451 

### 7.0 Agg re gate Ex po s ure / Risk Characterization In accordance with FQPA, H ED mu s t cons ider and aggregate pesticide expos ures and risks from three major sources: food , drinking water , and residential exposures. Because there are no uses for flutriafol wh ich result in residen tial ( non- occ upati ona l ) exposu r es, the aggre ga te assessment need on ly consider food and water. S in ce the dietary expos ure analysis included both food an d water , the discussion and exposure estimates presented in Section 5.4 represent agg regate acute and chro nic exposure to flutriafol and those metabo l ites id e ntifi ed as bein g toxico logicall y iden ti cal to flutriafol. A ll aggregate flutriafo l risk estim ates are not of concern to HED. Application of flutriafo l also res ults in expos ure to T and T AfT AAITLA. These compo und s are cons id ered to be tox ico logicall y different from flutriafol. HED conducte d an aggregate risk assessment for these compounds with the resulting exposure estimates less than HED ' s LOC ( D 426493, T. Morton , 9-Apr

- 20 I 5). 

### 8.0 C umulati ve Ex po s ure/Ri sk C h arac teri za tion F lutriafol i s a member of the tri azo le-containi ng class of pesticides. Althoug h conazo les act similarly in plants (fungi) by inhibitin g ergostero l b iosynthesis, there is not necessarily a relationship between their pesticidal activity and their mec hanism of toxic i ty in mammals. Structura l simi lariti es do not constitute a common mechanism o f toxicity. Ev idence is needed to establish that the chemicals operate by the same , or essentially th e same, seque nce of maj or biochem ical even ts (EPA, 2002). In conazoles, howev er , a variable pattern of to x i co log ica l responses is found; some are hepato to xic and hepatocarcinogenic i n mice. So m e i nduce thyroid tumors in rats. Some induce developmental, r eproducti ve , and neurological effects in rodents. Furthennore, the conazo les produce a diverse range of biochemical even t s incl u ding a lt ered cho lestero l levels , stress responses , and altered DNA methylation. 

### It is not clearly understood whether these biochem ical eve n ts are directly connected to the i r toxicological o utcomes. Thus, there is c urrent l y no evide nc e t o ind icate that conazoles s h are co mm on m ec hani s m s of to x ic it y and EPA is not fo ll owing a cumulative risk approach based on a commo n mechanism of toxicity for the conazoles. For information regarding E P A ·s procedures for cumu lating effects from substances found to h ave a common mec h a nism of toxicity, see EPA's webs ite a t http: // www.epa.gov/ pesticides/ c umul ative.

Page 1 9of3 1Flutriafol Human H ea lth Ri s k Assessment 0422451 

### 9.0 Occupation a l Ex posur e/ Ri s k C haracteriz a tion 0426919, K. Lowe, l-Sep-2015 

### 9.1 Handl e r Ri s k A ssess m e nt Based o n the anticipated u se patterns , and th e current labe li ng regard in g ty p es of eq uipm e nt and t ec hniques that can be u sed, occupational handler exposure is expected. T he follow in g exposu r e sce n a rio s wo uld b e ex p ec t ed: ( 1 ) mi x in g/ loadi ng liquid s fo r aer ia l and airb last app li cations; (2) app lying sprays v ia aerial and airb last equipme nt; and (3) flagging for ae ri a l app li cations. Th ese s cenar ios ha ve a lr eady b ee n assessed at th e propo se d maximum appli catio n rate in a previo u s assessment for other regi s t ered c rop s of flutri afo l (04162 1 3, K. Lowe , 24- J an-2014), and no ri sk esti m a tes of conce rn we r e identified. T he d e rma l a nd inhalation combined MOE s were not of co nc e rn to H ED (i.e
. , MOE 

### 2: 100) at base lin e and wi th the u se of gloves, as i s required o n the propo se d label. Combined occupational handler MOEs ranged from 280 t o 30,000 for ae rial and a irbl ast app li cations with the use of g loves by m ixers/loaders
. 

### 9.2 Post-App li cation Risk Assessment HE D uses the term post-applicati on to desc ri be exposures that occur when i ndividuals are present in an enviro nm e nt t hat h as been previou s ly t rea te d with a p es ticid e (a lso refe rred to as re-entry exposure). Suc h ex posures may occur when workers e nt er prev ious l y treated area s to pe r form job f uncti ons, includin g activities r e la ted to c r op produ ction , suc h as scou ti ng for pest s or harvestin g. Post-app li cation exposu re levels vary over time and depend o n s uch thin gs as the t y pe o f activity , the n at ure of the c rop o r targ e t that was trea ted , the type of pe s ti cide app li cation, and the chem icar s degrada ti on properties. In addition, the timing of pesticide ap pli cat io n s, relat ive to harvest activ i tie s, can g reatly reduce the potential for post
- app li cat ion exposure. 

### 9.2.1 Inh a l atio n Po s t- Applic a tion Risk Assessment There are multipl e potent ial sources of post-application inhala t ion ex p osure to indi v idu a l s performin g ac ti v iti es in previ o usly tr eate d fi elds. These poten tial sources include vo la til ization of pesticides and res u spe n s ion of du sts and/ or partic ul a t es that co nt a in pestic ide s . T h e age ncy so u g ht exp e rt advice and input on issu es related t o volatilization of pest icides from its FIFRA SAP in December 2009, a nd receiv e d th e SA P 's fi n a l repo rt on March 2, 20 10 ( http ://www.epa .gov / sc ip o ly/SAP/ m ee ting s / 2009/120 I 09meeting.html). The agency has evaluated the SAP report and h as deve l oped a Vo lat ili za ti o n Sc r ee nin g Tool and a subsequen t Vo lat ili zati on Scree nin g Ana lys i s (htt p : // www .regulations .gov /# !docketDetai l : D = EPA-HQ-OPP-2014-0219). D urin g Reg i s trati o n Review , th e age ncy will uti l ize thi s a n a lysis to determine if data ( i. e. , flux st udie s, route-specific inhalation toxico log ical s tudie s) o r furt h er ana lys i s is required for flutriafol. In addition , the Age ncy i s cont inuin g to eva lu ate th e availab l e post
- applicat io n inhalation exposure data genera t ed by the ARTF
. Given these two efforts, the Agency will cont i nue to id entify the need for a nd , s ub se quently, th e way to incor p orate occ up at iona l post-app l ication inh alation exposure into the agency' s risk assess ment s. A lth o u gh a quantitative occ up at iona l post-app li cat io n inh a lat ion exposure assess me nt was not performed , an inhalation exposure assessment was performed for occupational/commercial handlers w hi c h resu l ted in e xposu re less the H ED's LOC (see Sect ion 9.1). Handler expos ure re s ultin g from application of pesticides o utd oo rs i s likel y to result i n h ig her exposure than post-application exposure. T h e r efo re, it i s expected that these h a ndl e r inh a l ation exposure es timates wou ld be protective of most occ up ational post-application inha lation exposure sce n ar ios. Page 20 of3 IFl u tria fo l Human Hea lth Ri s k A ssess me nt 0 422 4 5 1
9
. 2.2 Dermal Post-App li cati on Risk Assessment S ho rt- and int e rm e diate po s t- a pplication de m1al exp os ure i s anti c ipate d with th e ex pected sce narios , e xp os ures, and MOE s summarized in T a bl e 9.2.2. l. A ll s c e nario s res ulted in MOE s greater than th e LO C of 100 ( ran g ing from 5 1 0-4200) o n day 0 (1 2 hours afte r a pp li c ation ; propo s ed R E I ) and , th e refo re , are n o t o f con ce rn to HED. S in ce c h e mi c al- s p ec ific d a ta are not a v ail a bl e , th e ex p os ure es tim a tes wer e ca lc ulated u s in g d e fault di s lo dgeabl e fo liar residu e ( DFR) as s umption s ( see b e lo w )
. Tab le 9.2.2.1: Occupat iona l Post-app li catio n Non

- Ca ncer Exposure and Ri s k Estimates for F lu tr iafo l
. T r a n s fer Pro p os ed D e nn a l Do s e MO E 3 C r o p/ Si t e Act iv it ies C oeffic ie n t Appl ica ti o n Rat e DF R ' ( m g/k g/ d ay) 2 ( L OC = JOO) ( c m21h r ) ( lb a i / a c r e) Short

- and Intennediat e -t e nn T ran s plantin g 23 0 0 .0 018 4 , 200 H and weedi ng , S tri pp in g , 640 0.004 9 8 1 , 500 Ho p s Scou t ing , T y ing(f r a in ing 0
. 11 4 0.32 M ec h a ni ca ll y -a ss i ste d h a rves tin g 1.400 0
. 011 690 Irri gat ion ( h a nd

- s e t ) 1 , 900 0
. 0 1 5 5 10 1 D FR

- Apphcatt o n Rat e x F x ( 1 -D )' x 4
. 54 E 8 μ g/l b x 2
.4 7F. -8 a c re / cm 2 : wher e F = 0. 25 and D = 0
. 10 per day . 2 Dai l y De rmal Dose = IDF R ( μ g/c m 2 ) x Tran s f e r Coe ffi c ieit x 0.00 1 m gl μ g x 8 h rs/ day x dermal a b so rpti o n ( 21 %) ] + BW ( 69 kg ). 3 M O E= P O D (7
. 5 m g/kg/da y) I Dail y Dcnna l Dose. 

### DFR: A s indi c at e d a bove , a c h e mical s p ec ific DFR s tud y i s not av a ilable. In a cc ordance with 40CF R158 , D F R d a ta are re quire d for a ll occ upationa l (e.g. , crop , nurse ry , g ree nh o u s e u se s it es) o r re s idential (e
. g. , o rnam e nt a l a nd v e ge t abl e g ard e n s , p ic k y our own farm s , r e t a il tree farm s) u se s th a t c ould res ult in po s t- a pplicati o n ex p os ure to fo li a ge. In th e a b se nce o f c he mical- s pe c ific DFR data, EPA u s es default va lue s . Th e 

### 20 12 S tandard Operating Procedur es .f o r R esid e ntial P es tic id e Ex p os ure Assess m e nt includ es a n anal ys i s of a numb e r of DFR s tudi es , which re s ult e d in the s e l e cti o n of a rev i se d de fault va lue s fo r th e frac ti o n o f th e a pplicati o n r a te ava ilabl e fo r tran s fe r a ft e r a fo li a r appli ca ti o n (FAR)
. T hese v alu es a r e b as ed on a n anal ys i s of l 9 DFR s tu d ies. S in ce th a t tim e, th e A RTF ha s s ubmitted information ( MRJD 49 2992 01) that cor rects an appli ca tion rat e e rror mad e in th e origina l s ubmission o f "A RF0 3 9

- Determination o f Dermal a nd Inh a l a ti o n E x p os ur e to Ree nt ry W o r ke rs During C hrys anth e mum Pinchin g in a Greenh o u se" ( E P A M RJD 4 534 4 50 1 ). As a r es ult , th e ra n ge of F A R va lu es was r ev i s ed fr o m 2%

- 89 % to 2%

- 47 %
. In the d a ta , a large r a nge o f tran sfe ra bilit y i s ob se rved and thi s variability can potentially b e attributabl e to man y factor s s uch a s acti ve i ngredient ; fonnulation ; field cond i tions in the st

u d ies ; we ath e r co ndition s (e
. g . , humidity); o r man y o th e r diffi c ult to quantif y fac to r s . A lth oug h w itne s sed acro ss multipl e c he mi cal s , thi s ran ge in F A R va l ues i s not ex p ec t e d w h e n co n s ide rin g D F R d a ta fo r a s in g le c hemi ca l. A t thi s tim e , the ART F s ubmi ss ion did not alte r th e se lect io n of 25 % a s the rea s on a b le, hi g h- e nd default va lu e. Becau se DFR dat a are not avai labl e fo r flutri a fol , E P A i s usin g th e d e fault valu e of 2 5 %
. A lthough th e re ma y b e a s mall degree o f un ce rt a in ty in th e u se o f th e defa ult DFR va lu e for flutri afo l ( i. e. , th ere i s a small c hance th a t the F A R va lu e m ay excee d the applic able defa ult va lu e) , it i s li ke ly th a t th e he alth

- p ro tec ti ve a s p ec t s of E PA ' s occ up a ti o nal po s t-application a ssess ment me thodology w ill more th a n c ompensat e fo r thi s p o te ntial un ce rtainty
. For example , wh e n ass e s s in g re sidential and occupati o nal postap pli cation ex p os ur e to gard e n s and orn a me ntal s , EP A ass ume s th e followin g: ex po s ures o c c ur to ze ro- d ay ( i. e .. d ay o f appl ica ti o n ) res idu es ev ery d ay of the asse ss e d ex p os ure duration ( i. e. ,

P agc2 1 o f 3 1Flutriafo l Human H e alth Ri s k A ssess ment 0 422 4 5 1 E PA ass um es that no di ss ip ati o n o r d eg rad a ti o n oc curs , it d oes n ' t rain , e tc.); indi v idu al s pe r fo rm the sa me po s t-app li cation acti v iti e s performed in the tran s fer co e fficient s tudy day after d ay ( e. g., wee din g, ha rves tin g , prunin g , e tc . ); and indi v idu a ls e ngage in th ese p os t- a pplic ati o n a cti v iti es for a hi g h- e nd a m o unt o f tim e eve ry day ( re prese nte d b y data refl ec tin g tim e spe nt ga rd e nin g base d on s urve y dat a). Gi ve n the c o n servati s m s di sc u sse d ab ove and th e p ot e nti a l c omp o undin g n a ture of th ese con se rv ati s m s, E PA i s able to re ly upon the calcu lated ex posure es timat es with confiden ce that exp os u re i s no t b e in g und e r es tim a te d
. Sin ce the hi g hes t estim a ted o cc upational post -applicati o n ex po s ur e u s in g de fault DFR v a lu es for flutr iafo l i s minimal in co mp ari so n to th e LO C ( i. e . , th e c alcul a te d M O E i s g re ate r than 2 tim es hi g he r than th e LOC , MO E = 5 10 co mpare d to th e LO C of 100 ); E P A i s wa i v in g the 4 0 C FR DFR data re qui rem e nt. In thi s in s tance , it i s unlik e ly th a t c hemi ca l-spe c ific DFR data wou ld be ne e d e d to ft 111her re fin e expos u re assess me nt s o r w oul d a dd ap p rec iabl y to o ur ove rall und e r s tandin g o f th e ava ilabili ty o f di s lodg e abl e fo liar p es ti c id e res idu es fo r flutri afo l. 9.2.2 Restricted E nt ry Interval The REI sp e cifi e d on the prop osed l ab e l i s ba sed on th e a c ute tox i c it y o f flutriafo l. Flutri a fol has low ac ute tox icity v i a th e ora l , de rmal a nd inh a lati o n routes (T ox ic it y Categ ori es Ill and 

### T V). F lutri afol i s minim a ll y irritatin g to th e eyes (Tox ic i ty Cat eg or y Ill ) and i s n o t a de rm a l irritant ( To x ic ity Category 

### IV )
. Flutriafol wa s not shown to b e a s kin se n s iti z er when te s t e d in g u in ea pi gs (B uehl e r m et ho d ). S ho rt
- and int erme di a t e -t e rm p os t- a ppli ca ti o n ri s k es tim a t es we r e not a c onc e rn on d ay 0 ( 1 2 hour s fo ll o win g appli cati o n ) for a ll p ost- appli cati o n ac ti v ities. U n de r 40 CFR 1 5 6.208 ( c ) ( 2) (iii ), ai 's cl as sifi e d a s Acut e Ill or 

### TV for acute dermal , e ye irri ta tion a nd primar y s kin irri ga ti o n are ass ig ne d a 12- ho ur RE I. The re for e , th e ( 15 6 s ub part K] W o rke r Pro tec tion S tat e me nt int e rim R E I of 1 2 hour s i s a d equ a t e t o p ro t ec t a g ri c ul tural worke r s fro m po s t-app l ic a ti o n exp os ures to llutriafol.

RDI : RABI ( 1 3- May - 2 01 5 ) App e ndix A. T ox icology Profil e and Exec uti v e S ummari es App e ndix B. C h emi c a l Nam es a nd S tru c ture s App e ndi x C
. Ph ys ic a l / C h e mi ca l Pro perti e s

P age 22 of3 IF lutri afo l Hum a n H ea lth Ri sk A ss ess m ent 0 42245 1 

### A pp e ndi x A. Toxi co lo gy Profil e a nd Exec uti ve S umm a ri es T he r e quire me nt s (4 0 CFR 1 58. 3 40) fo r food use s for flutriafo l are in Table A. 1. U s e of the n e w g uid e line number s d o e s no t impl y that the new ( 1 99 8 ) g uid e lin e prot oco l s we re u se d.

Ta bl e A. I: St u dy R e quir e m e nt s for F oo d Uses fo r Flu tria fol
. S t udy Technica l Re quired Sa ti s fi e d 870. 11 00 Acute Ora l Toxicity yes yes 870 .1 200 Acute Dem1al Toxicity yes yes 870 .1 300 Acu te Inh a l ati o n Tox i city yes yes 870.2400 Pri mary Eye Ir r i tation yes yes 870.2500 Primary Demial Irr itat i o n yes yes 870.2600 D e rma l Se n si ti zati o n yes yes 870.3 1 00 Oral Subchron i c (rodent) yes yes 870.3 1 50 Oral Subchronic (nonrodent) yes yes 870.3200 2 1- Day D e m 1a l yes yes 870
. 3250 90-Day Demia l no 

### - 870.3465 90-Day I nhalat ion no 

## - 870.3700a D eve l o pm e nt a l Tox i c it y ( rod e nt) yes yes 870.3700b Devclopmen1al Toxicit y (nonrodent) yes yes 870.3800 Reprod uction yes YCS 870 .41 OOa C hro ni c Tox i c i

ty ( rod e nt ) yes yes 870.4 1 OOb Chronic Toxic i ty (nonrodent) yes yes 870.4200a Oncogen i city ( rat) yes yes 870.4200b O ncoge ni c ity ( m o u se) yes yes 870.4300 Chronic / Oncoe.enicity yes yes 870.5100 Mutagcnicity

- Gene M utat i on - bacte r ial yes yes 870.5300 Mut age ni c ity - G e n e M uta ti o n - ma mm a li an yes yes 870.5xxx Mutagen i city

- Structura l Chromosoma l Aberrations yes yes 870.5xxx Muta_ge ni city-O th er Gc no toxic Elfec ts yes yes 870.6 1 OOa Ac ut e De l ayed Ne u ro tox i c it y ( he n ) no 

### - 870.6100b 90-Day eurotoxicity (hen) no 

### - 870.6200a Acute eurotoxic ity Sc r eening B a tt ery (rat) yes yes 870.6200b 90-Day Ne u rotox i c i

ty Sc ree nin g B a t1 ery ( ra t) yes yes 870.6300 Develop. Neurotoxicitv no 

### - 870.7485 General Metabo li sm yes yes 870.7600 D e rm a l Pe ne trat i on yes yes 870.7800 l mmunotoxicit y yes yes



### -- Tab l e A
. 2 : Ac ut e T ox i c i ty Pro fil e - F lutri afo l.

Guideline No. Stud y Type M R JD(s) Res ult s Tox i ci t

y Cate.izory 870. 11 00 Ac ute o r a l ( rat ) 4709 0336 LD so = I 1 40 mg/ l rn ( M ): 1 4 80 m g/ k e. (F) Ill 870. 1 100 Acute oral ( m ouse) 47090335 1 LD so = 365 mg/kg bw (M): 179 mg/kg bw ff) II 870.1200 Acute derma l (rat) 478610 1 LD so>2000 mg/kQ bw 111 870. 1 300 Ac ute inh a la ti o n fra t) 47090338 LC so > 5 .20 ml!.IL IV 870.2400 Primarv eve irrita tion (rabbit) 47090339 Minimally irritatinJ?. Ill 870.2500 Primary de rm a l irri ta ti o n (rabb i t) 4709034 1 No t a d e nn a l irrit ant IV 870.2600 De rm a l se n s iti za ti o n ( m o u se) 47090343 Not a**se it** **~** 

## -

P

age 23 of3 IFlutriafol Human H ealth Ri sk Assessment 0 422451 N ote: I t i s r ecognized that so m e s tudies in the tlutriafol database have conservative NOAEL/LOAEL va lues that are ba sed on effects that are n ot co n s i dered adve r se according to c urr e nt HEO p o li cy (e
. g . , body weig ht ga in)
. These updates, however , wo uld resu l t in hi gher NOAEL/LOAEL values and would not impact the se lected e ndp o ints . Consequent ly, g i ven the c urr e nt risk pi c tur e for fl utr iafo l , the Agency d id not find it necessary to upd ate th ese stud ies at this time.

Ta bl e A.3: S ub c hr o ni c and C hroni c To x ic ity a nd Ge n o to x ic it y Profile- Flutr iafol. G uidelin e No. S tu dy Type 870.3050 28-Day oral toxicity (ra t) MRID No. (year) / C lassilication /Do ses R es ults 4 7090344 ( 1982 ) fNOAEL = 800 ppm (80 mg/k g/day). Acceptable/ non- g uid e line**~OAEL** = 2000 ppm (200 mg/k g/ day). based on liver 0. 100. 300. 800. 2000. or toxicity ( increased wei g ht, centrilobular h epa t occ llular 5000 ppm (0. 10. 30. 80. 200. l hype nroph y. fatly change. hydropic degeneration. s mo o th and 500 mg/kg/day) endoplasmic reticulum proliferation. and increased aminopyrine- -demethylase activity) in both sexes and decreased body-weight ga in and food consumption in male s.**1--~~~~4-~~~~~~~-t-~~~~~~~~~~~~~~~~~~~~~~~ -~**  870.3100 1 90-Day oral toxicit y 1 47090345 ( 198 2) :NOAEL 

### = 200 ppm ( 14/ 22 mg/kg/day in M /F).

870.3 150 (rat) j Acccptablc/guidclinc LOAEL = 2000 ppm ( 1581145 mg/kg/day in M/F), based on

90-Day oral toxici ty ( do g) 

# l o. 20, 20?· or 2000 ppm decreased body-weight ga in. decreased food consumption M: 0 , l. :i

. 14
. and 158 and liver tox icit y (increased ab s olute a nd adju s ted liv e r 

## l mg/kg/day) weights. increased endoplasmic reticulum proliferation in I': 0. 1.6
. 22. and 1 45 the mal es, and increased APDM activity). mg/k.e,/day 47090346 (1982) Acceptab l e/guide lin e 0. I. 5. or 15 mg/kg bw / day iNOAEL = 5 mg/k g/ day. LOAEL = 15 mg/kg/day. based on adverse liver findings (increases in organ weight, alkaline pho s phatase. aminopyrine N-demct hy lase activity, and in cidence of 

# l hemosiderin-ladcn KupfTer cell s) in both sexes. spleens with hem os id erin content slight ly higher than controls in 

# I the males. and decreased cumu l ative body-we i ght ga in s and in creased tril!.lvcerides in the females. 870.3200

870.3700a

870.3700a 28-Day dcnnal toxicity (rat)
Pr

ena tal developmental (rat) 47090347 (2007) Acceptable/guideline 0. 250. 500.o r 1 000 mg/kl!/ day 47090349 (1982) Acceptable/guideline 0. I0 , 50. or 125 mg/k g/ da

y

Prenata l developmental 4 752 1303 (2008) (rat) Acceptable/ guideline 0. 2. 5. 10. or 755 m g/kg/ da y

Page 24 of3 I NOAEL 

### = I 000 mg/kg/day. 

# I LOA EL was not es tabli s hed
. Maternal NOAEL = 50 m g/kg/day. LOAEL = 125 mg/kg/day, base d on increased incidence of ventra l/ge nital sta ining of th e fur and decreased matern a l body-weight gains and food consumption. D evelopmental OAEL 

### = 10 mg/k g/ day . LOAEL 

### = 50 m g/kg/day, based on delayed ossilication or non-ossification of the s keleton in the fetu ses. M ate rnal NOAEL 

### = 10 mg/k g/day. LOAEL = 75 mg/kg/day. based on decreased body-weight gains and food consumption. Deve lopme ntal NOAEL = 10 m g/kg/day. LOAEL = 75 m g/kg/ day. based on increased late

're s orption s; malfonnations (cleft palate and multiple hyoid malformations) and variation s in the hyoid: va riati ons in th e maxilla/mandible. rudimentary and lo ng cervical rib s . pe lvic g irdl e, and radiu s/ ulna; numerous ske l etal 

# I retardation s detail ed ab ove and corresponding decrease in fetal**weigl ~**  IFlutriafol Hum a n H ea lth Ri sk Assessment 04 2245 1 Tab le A.3 : S ub c hro ni c and Chronic Toxicit and Ge n otox ic i t Profile

- Flutr iafol. Guide lin e No. Study Type MRID No. (year)/ C lass ification /Dose s Results 870 .37 00b

870.3800 P renatal developmental 4 7090350 ( 1982 ) (rabbit) Accep tab l e/ g uid e lin e 0. 2. 5. 7 .5. or 15 mg/kg/ day

2-gen. reproduction and 4 7090351 ( 1 986) fertility efTec t s Acceptable/ g uid e lin e (rat) 0. 60. 240. or 1. 000 ppm M: 0 , 4.8. 20.6. and 88.7 

## l mg/kg/day) F : 0. 5.5, 2 1. 9. and I03 mg/kg/day Maternal NOAEL = 7.5 mg/ kg/day. LOAEL = 15 mg/kg/day
. ba se d on d ec reased co rrec ted and uncorrected bod y -weight gai ns and food consumption. Devel op mental OAEL 

### = 7.5 mg/k g/day. LOAEL = 15 mg/kg/ day. based on decreased numb e r of li ve fetu ses. complete litter re s orption s and increased post
im lantation loss. Par e ntal /Systemic NOAEL 

### = 240 ppm (20 6 / 2 1 9 mg/ kg/ day [M /F]). LOA EL 

### = I 000 ppm ( 88. 7 II 03 mg/ kg/day [tvVF]) based on decreased body-weight gain s and food consumption and on efTects o n th e li ver (i ncr eased li ve r we ig ht s, ce ntrilobular 

# I hypertroph y . and fatty change). R e produ c ti v e OAEL = 1000 ppm (88.7/ 103 mg/kg/day [ M/Fl). LOA EL was n o t de t e rmin ed. Off sp rin g NOAEL = 240 ppm ( 20. 612 1.9 mg/k g/ day [M/F]). LOAEL 

### = I 000 ppm (88. 7/ 10 3 mg/kg/ day [ WP]) based o n decreased live birth index and l itter s ize and on efTects on**.,,._--------r-----------1------------i- th** **e_h ·v** **cr fa** **y_c han~ge** **_l_ va** **liz ~_ti_o** **n) --** **--- ------i** 

1 870.3800 2-gen
. reproduction a n d 48 1 9692 1 , 48 1 96922 (2009) Parental /S ystemic NOAEL = 15 0 ppm (9 / 10 .8 m g/kg

870.4 1 00

870.4200 fert ilit y effect s bw/ day [M/F]). (rat ) Acceptable / guideline Par e n tal/S ys temi c LOA EL = 300 ppm ( 18. 2122.6 mg/kg

C hro ni c toxicity ( I year: dog)

Carcinoge nicity ( mou se) 0. 30. 80. 1 50, 300, 1 000 ppm bw/day [M / FJ) bas ed up o n increased relative liver weights. 0 , 1 .8/2.2. 4.8/ 5.85 , 9 / 1 0.8, fatty deposits in th e li ver in both sexes as well as 1 8.5/ 22.6. and 62.8 / 77. 1 hepatoc ellu lar hyp ert roph y in male s. mg/kg bw / day [ WFJ Repr o du ctiv e NOAE L = 300 ppm ( 18 .2 / 22.6 mg/kg bw/ day [ M / F]

.

4 7090353 ( 1 988) Acceptable / g uideline 0. I , 5. or 20 mg/kg/day Reproductive LOAEL was not observed. Off s prin g I QAEL = 1 50 ppm (9110.8 mg/kg bw/ day [M /F]). Off s pring LOAEL == 300 ppm ( 1 8.5/ 22.6 mg/ kg bw/ day f fVV FJ) based upon increased pup m ortali ty in the F l pup s at the fir st litter check and 0- 4 oostnata l da""vs

_

.______ -i NOAEL = 5 mg/ kg/day. LOAEL = 20 mg/k g/day
. based on: adverse liver findin gs (increased liver weightS. inm:ased centrilobular hepatocytc lipid in th e li ver, a n d in c reases in a lkaline phosphatase. a lbumin a nd trigl yce rides). increased ad rena l cortical vacuolization of the zona fasciculata. and marked hemo s i deri n pigm e ntation in the li ve r and spleen in both sex es: mild a nem ia (characterized by decreased hemoglobin. hemat ocri L and red blood ce ll count) in the male s: and initial body weigh t losse s, decreased cumulative body-weight gai n s. and increased ad re nal weigh t s in th e fema l es. 47090354 ( 1988 ) NOAEL 

### = 50 ppm (5.917.4 mg/kg/day in M/F). Acce pt ab l e/ guidel in e LOA E L = 200 p pm (24 /3 1 mg/kg/day in WF), based on 0 ( two con trol gro up s)
. 1 0. 50. h e p a totoxicity (increased fatty change) in bo th sex es. or 200 ppm M : 0, (0, I.I , 5.9. and 24 mg/kg/day) F: 0. 1.4. 7.4. and 3 1 m!?/kg/dav

Pa ge 25 ofJ I N o e v id e nc e of carcinogenicity.Flutriafol Human Hea lth Ri sk A ssess ment 0422451 Tab l e A. 3: S ubchr o n ic a nd C h r o ni c T ox i c it y and Ge not ox ic itv P ro fil e - F lut riafol. Guideline No. S tud y Type MRJD No. (year)/ Re s ults I C lassification /Doses I 870.4300 Comb in ed C hronic 47090352 (1986) NOAEL

- 200 ppm ( I 0.0/ 12.2 m g/ kg/day in 

# l Toxicity/ Acceptable/guideline male s/ female s)
. Ca rcino ge nicit y 0. 20 , 200. or 2000 ppm LOA EL = 2000 ppm ( I 02/ 1 22 mg/k g/ day in 

# I ( rat) M: 0. 1.02. 10 .0. and 102 male s/ female s), based on adverse liver effects (increased mg/kg/day) liver weights . fatty change. bile duct F: 0, 1.27 .12.2, a nd 122 prolifcration / cholangiolarfibrosis. hemosiderin mg/kg/day ' accumulation in Kupffer cells and cemrilobular hy pertrophy). and clinical chemistry finding s. No ev id e n ce o f c ar c in oge ni c i ty
. 870.5100 In v itro Oactcrial Gene 4 709040 I ( 1988 ) There were no mark ed increases in th e mean number or Mutation (Sa lm onella Acce pt able / guideline rcvcnant s/ plate in any stra in
. Ther e was no evidence of typhimurium) / O. 1.6. 8. 40, 200. I 000. or induced mutant colonies over background. mammalian activation 5000 11g/plate (Trial I ) or 0. gene mut atio n assay 8.40.200. 1 000. 2500 .or 5000 11g/p late (Trial 2); Both trials were perform ed w / wo S9 -acti vation 870.5300 I n vi tro Gene Mutation 4 7090402 ( 1 986) There was a dose-re lated in crease in mutant frequency (7.0- assay in mouse Acceptable/ guideline 9.0 x I 

### o ·S treated vs. 3.0 x I 

### o ·S controls) and absolute lymphoma cell s 0. 1 0
. 33. 1 00
. 333. or 1000 mutant numbers (70- 1 48 colonies/plate vs. 63 control s) at 11g/mL (+S9, Trial I); 0, 150 , I 00 μ g/ mL and above in Trial I and a mark ed increase in 300. 450. 600. or 750 11 g/m L mutant frequency a t 750 μ g/ mL (6. 5x 10· 5 trea ted vs. 1.2 x (-S9, Trial I ): O. 15 0. 300. 1 0 -s controls) in Trial 2 attributable to severe cytotoxicity 450. 600. 750. 900. I 050, or (2% relative s urvi va l). I lowever , th e increases in mutant 1 1200 μ g/ mL (+ S9. Trial 2): or frequenc y did not achieve th e thresho l d value for a positive 0. 200. 300. 400. 500. 600. l 'e.pooso ( > I 0 x IO ·' ) io eiUo« t<i•I Md th"< 

## w" oo 700, or 800 μ g/ mL marked increase in absolute mutant numbers at 750 11 g / mL 

### I (

- S9
. Trial 2) in Trial 2. I n the absence of S9. there were no mark ed !increase s in mutant frequenc y or absolute mutant numbers compared to controls in either trial. T here was no convincing evide nc e of induced mut a nt colonies over backg round in the presence or absence of S9-activation. 870 .5300 I n vitro Ge ne Mutation 481969 1 8 (2006) The muta gc nicity criterion ( threshold ) of 126 co loni es per assay in mouse Accep tabl e/guide l ine I 06 cells above the so lvent control was not reached for any lymphoma cell s 0. 25. 50. I 00. 200. 400. and valid data at any te s t concentration
. with or without 600 11g/mL (±S9. Trial I ): 0. metabolic activation. Although linear regre ss ion analysis 12.5. 25. 50. I00. 200. 300 or found a s ig nific ant (p < 0.05) dose dependent trend of the 400 μglmL (-S9. Trial I ): 0. mutation frequency in Experiment 1 (culture I. with 200.300, 325,350. 375. o r m e tabolic activation). Experiment 2 (c ulture I )

. and 400 μ g/ mL (+S9. Trial 2) Experi ment 3 (c ultures 1 and 2), these s tati s ti ca l re su lt s (-S9. Tr ial 2) were considered biologically irrelevant becau s e the thre s hold for mutagc nicity wa s not exceeded and all ab so lute va lu es were within the range of hi s to rical n ega tiv e and solvent controls. 870.5375 I n vi t ro Mammalian 4 7090403 ( 1989) No s ignificant incre ases in the numb ers of cells with Cyto genetics Acceptabl e/guideline aberration s (exc ludin g gaps) were obse rved in eit h er donor (C hromosoma l 0. 25. 1 25. or 250**~1g/mL** (+/

- 

# r th e pre se nce or absence of S9. There was no evidence of Aberration A ssay in S 9) chromosome aberrations induced over background in th e Hum an Peripheral l pre sc nce o r absence of S9-activation. Blood Lymphoevtes} 870.5385 In vivo Mammalian 47090404 ( 1982 ) i: rhere was n o evidence of chromosome aberration induc ed 

## I Cytogcnetics

- IBone Acceptabl e/ guideline over background. Marrow Chromosomal 0. 15
. 70. or 150 mg/kg Aberration Te s t

--- 870.5395 In vivo Mammalian 4 7090405 ( 1986 ) D ecreased (p < O.O I ) polychromatic eryt hrocy te to I Cy to genet ic s - Acceptab le / guideline nom1ochroma1ic erytJ1rocytc ratios (PCE: CE) were Erythrocyte 0. 93.8. o r 150 m g/kg ob s erved in both do s es at all time points. indicatin g th at the Micronucleu s Assay in te s t material was toxic to th e bone marrow. There was no Mice significant increase in the frequency ofmicronucleated po l yc hromatic erythrocytes in bon e marrow after any 

# I treatment time
. Page 26 of3 IFlutriafol Hum an H ea lth R i s k Assessment 0422451 Tab l e A.3: S ubchr o ni c a nd C hroni c Toxicit an d Gcnotoxici Guide line No. S tud y Ty p e MR ID No. (year) / C l ass ification / Do ses 870.5450 Dominant Lethal Assay 4 7090406 ( 1 982)

- Mice Acce ptabl e/guid e lin e 0. 25, 50. o r I00 m g/ kg/day ( t o tal dose s of 0, 125. 250. or 500 mg/kg) Profil e - Flutriafol. R

es ults Monality (3/15 males) was noted a t 100 mg/kg/day durin g dosing
. S li g ht decreases (p <0.05) in body wei g ht were obse r ved ai 50 mg/kg/day and above during d osi ng. There were no treatment-related effects on fcnility
. mean number of implantalion s. o r the numb er of ea rl y or l a te deaths. T here was no tim e-re l a ted po s itive response of increased 1----

- --+- - ------ - -1--

- -- -- -- - -' l"-- re

=- - --=

o-=-

r ,.1:..;;os t-im lantation loss com arcd to controls.

870.6200a

870.6200b Unsched uled DNA 47090407 (2003) Sy nth es i s in Primar y Acce ptabl e / g uidelin e Rat 0
. 250. 500. o r I000 mg/kg I lepato cy tes/Mammalia n Cell
Acute neurotoxicity 47090408 (2005) sc ree nin g batt e ry Accep tab l e/g uidel in e 0. 125
. 250
. or 750 mg/kg

Subchronic 4 70904 I0 (2007) Neurotoxicity

- Feeding Acce ptabl e/ g uidelin e S tud y in Rats 0. 500. 1500. or 3000 ppm The net nuclear g rain (NNG) cou nts in the treated anima l s (

- 3.42 to - 2. 64) were well be l ow the thres hold of <:: 5 NNG needed for a positive respon se. and no increase in the mean percent of cells in repair was observed. There was no ev id ence that un sc heduled DNA sy nth es i s, a s de1cnn in cd by radioactive tracer procedure s [nu c l ear si l ve r g rain counts! was induced. NOAEL = 250 mg/kg. LOAEL = 750 mg/ kg. based o n dec reased body weight. body

- weight gain. absolute and relative food consumption. and clinical signs of toxicit y. indicative ofa moribund co ndition, in both se xes: deh y dration , urine- s tain e d abdomina l fur
. ungroomed coat
. pto sis. decreased motor activity. prostration. limp mu scle tone. muscle flaccidity. hypothermia. hun c hed po st ure, impaired o r l os t righting reflex. sca nt fece s; in male s: red or ta n pcrioral s ub s tance. chromodacryorrhca. chromorhinorrhea and lab ored brea thin g, and in females: pilocrcction a nd bradypnea. and s i g n s of nc uro to x i city: hunched po s ture in females and ataxia in ma l es. NOAE L = 15 00 ppm (84.3 / 97.6 mg/ kg/day f M/FI). LOAEL = 3 000 ppm ( 172.1 /185 .0 m g/ kg/day [M/FJ) based on decreased bod y -weight ga in. abso lut e and re l ative food (0 1

0. 28.9 / 32.6. 84 .3/ 97.6. and (o n sumption: and dec r eased hindlimb grip strength in 172. 1 /185.0 mg!kg!'.day [Mtr-1} ma l es.

Page 27 of3 IFlutriafol Human H ealth Ri s k A ssess ment 0422451 Ta b l e A.3: S ub c hr o n i c a n d C h r o ni c T ox i c ity a nd Ge n o t ox icit l'. P r ofil e - F lutri a fol
. Guideline No. S tud y Ty p e M RID No. (yea r) / R e s ults C lassification /Doses 870 .7485 Metaboli s m and 47090414 (2004 ). More th an 78% of the do se was recovered in th e bile and phannacokinetic s 47090412 (2006 ) urine. Absorption was simila r between sexe s a nd between (rat) J\cceptable/ guidc lin e s in g le and multipl e do se re g imes. Ab s orption is exten s ive. 5 or 250 mg/k g The dose wa s mo s tl y eliminated within 48 hours. Only 0
. 04

- 0.05% of the dose was fou nd in the expi r ed carbon di ox ide. Most of th e radioactivity was excreted in the b ile (47-79% of the do se). The excretion profile was s imilar between sexes. In th e blood. radioactivity partitioned into th e re d blood cells. In both sexes and all g ro up s . concentrations of r a dioactivity were re lativ e l y high in whole blood. liver. and kidn eys. Other organ s wi th high concentrations included the adrenal g land s. s pleen. a nd pituitary
. The di s tribution profiles w e re s imilar between s pecies. dose level. and sing l e vs. multiple do s e regime
. In 

## I th e whole blood. th e concentrations were proportion a l to th e do s e . Th e total am o unt of radioactivit y i so lated in the ti ss ues and carcass was < 1- 3 %
. Bioaccumulation w as considered unlik e ly. The parent was isolated in only trace amounts in th e urin e and fe ces and more th a n 19 metabolite s were i s ola ted. indicating ex ten sive metabolism. Metaboli s m profil e s were s imilar between sexes. The m e t a boli c profiles were s imilar regard l ess of th e m atri x (feces
. urine. o r bile). th e do s e. and th e sex. The primal) ' s ite fo r m e taboli s m was the 2- fluorophen y l rin g. The initial m e tabolic s tep was e poxidati o n foll o wed b y e ither rearrangement to form th e dihydrodiol i some r s o r to form hy droxy or clihydroxy m e tabolite s. The hy droxy l g ro up s on th ese prim a r y metab o lit es ma y then be either conjugated with g lu c uro nic acid o r methylated. A second. min or route for metab o li s m offlutriafol was via th e remo va l of th e triazole rin g to form 1- (2 nu o roph c n y l)-1- ( 4-fluor op hcn y l)- cthand iol. w hich i s then conjugated wit h glucuronic acid. 870 .7600 In v i vo dermal 4 70904 15 ( 200 6) Dermal ranged up to 15 .8% of th e applied do s e. penetration Acceptab l e / guideline Abso rpti on was minimal wi th o nl y 4 h of exposure. (rat) 1 0.002. 0.02. or 0.2 m g/c m 2 J\bso rbabl c radioactivity (radioactivity in th e s kin at the s kin were tes ted ( IO μl / cm 2 app lication s ite and th e adjacent s kin ) was minimal in l sk in ). and acnr al doses we r e g roups th at were exposed for I 0 h and evaluated for an 0.00208. 0.020 I. and 0.2154 additional 1 58 h po s t-t:xpo s urc. Thu s, a lm os t all of the m g/ cm2 s kin do s e i so lat e d in th e s kin wi ll be absorbed. Co n s id e rin g the sum of ab s orbablc a nd abso r bed do s es. 4

- 3 7 % of th e app lied clo se was r ecove red in the trea tment gro up s ( 11 %). Absorp tion rate cons tants were calculated as 0.236. 0. 1 90. and 0.072 h · 1 for th e 2
. 20. and 200**g/ cm** **2** dose g roup s . Ab s orption mechani s m s were sa turat e d at the high dose. The e liminati o n half-li ves were calculated to be 3 1. 30. and 37 h fo r th e 2. 20. and 200**~1 g/** **2** do s e group s . A maximum o f36.56 % of th e applied dose was noted as 

## I ab s o rbed/abso rb ab l e (o b served after 2 4 h exposure to 2 

## l μg / o m

' )

. Th o do.o '"" ; , >b s o,b<d/ob>o,bobk follow;"g' 

# I I 0 h exposure is 1 6.54%. 2 1. 3 1% and 11. 39%. re s pec ti v el y. a t 2. 20. a nd 200 u gl' cm 2 • 870.78 00 l mmun o to x icit y ( mic e) 48360301 (20 11 ) ! Sy s temi c NOAE L = 9.8 mg/k g/ day. --, Accep tab le/ guide l ine System i c LOJ\EL 

### = 46.8 m g/kg/day) base d o n increas ed 0. 50. 250. 5 00. I 000 ppm [FJ ab s o lute and relative li ve r weights a nd hematological 

# (0. 9.8. 46 .8. and 20 8 effec t s. mg/k g/ clay [F l lmmunotoxicity N OA EL = 20 8 m g / kg/ day. lm munotoxicity L OAEL was not e s tablished. 

## I

Page 2 8 of3 IFlutriafo l H uman H ea lth Ri s k Assess ment A ppend i x B. C hemica l Name s a nd S t r uctu res C omm o n n a m e

Flutriafo l

M I B

M28

1 .2.4

- Triazo le (I')

Triazolylalanine (TA)

Triazolylacetic acid ( T AA)

Triazo le lac ti c ac i d (T L/\)

I lydroxy nutriafol glucuroni de ( H FG: M 3) C h e mical n a me

( ± )

- a - (2-n uoropheny 1)-a-( 4

- nu orop hcny I )

- I// -I .2.4- t r i

azo lc- 1

- e th an o l

1- (2-nuoro

- 4

- h> ·droxyphcnyl)- I -( 4

- nu o rop hc ny l)-2

- ( I /-/-1 .2 .4-lri azo l

- 1

- yl)cthanol
glucoside of a nu tr ia fol metabolite
. p oss i b l

e a de r ivati ve hy d roxy l a tcd on o ne p heny l r ing
I H -1 .2.4

- tri azo l c

2

- am ino-3

-( I/-/-1 .2 .4- triazo l- lyl)propanoic acid

I /-/-1 .2.4 -t riawl -1- ylacctic ac i d

1 , 2.4-tri azo le- 1-l ac ti c ac i d

Page 2 9 o f J I F

F C he m ical s tru ct ure N

# <~NF 

# I '..:::::: h-

# o~

I N

## (~

N

- N**~** ,,,,;:. OH 

## I

H N-N 

# I( ) N F**~** ,,,,;:. OH 04 2245 1Flutri afo l Hum an H ealt h Risk Assess m ent 0 422 4 51 Co mm o n n ame C h e mi ca l n a me C h e mi ca l s tru ct u re
OH OH 

# 0 Dih yd roxy Outr iafo l ( DH F:



## -- F H M3c) 

## N:) 

# 0 

# 4 F

Flutriafol g lucuronidc (FG: M4 ) 

## - -

# ~~ ,o**~**

...**~~ ~**  Mcth oxy Outriafol g lucuron idc



### -- 

# o/ ( M FG: M7)

f 

# + on 0 F

lutri afo l s u lfa te (FS: M 1 0) 

## -- HO 

## 0

P

age 30 of3 IFlutriafol Hu man H ealth Risk Assessment 042245 1 

### Ap pendix C. Physical/Chemical Propertie s. Tab le C. l i s a su mm a ry of th e physical/chemical propert ies fo r flutri afo l. Flutr iafol has a low vapor pre ss ure a n d a low He nry ' s law co n s t a nt (9. 1 6 x I0

- 12 a tm m3 / m o l).
Tab l e C.l: Ph ys i cochem i ca l Pr o p e rtie s o f F lu triafol. Melting ooint/range 

### -- Not available p ll 6.1 in a 1% aqueous dilution CS P for F l utriafol T echnica l dated 3123 / 07 Density 0.99 g/c m 3 Water so lubilit y 95 m l?/ L at 20 °C At21 °C gL!, 1 .2-Dichloroethane 1 9

-20 Acetone 11 6 -135 Solvent so lubi l it y E th y l acetate 29-34 Methanol 11 5- 134 PP# 7177 I 97 administrative materials n-Heptane < 1 0 Xylene < 10 Vapor pre ss ure 4 x 1 0- 7 Pa at 20 ° C Di ss ociation con s tant, oK
. 2.3 at 25 °C Log(Kow) log P ow= 2.3 at 20 ° C UV/ visible absorption s pectrum 

## -- Not availab l e

Page 31 of 31