### UNITED ST ATES ENV I RONMENTAL PROTECTION AGENCY WASHING T ON , D .C

. 20460 OFFICE OF CHE MI CAL SA FET Y AND POLLU T ION PREVEN T I O N 

### MEMORA N D U M
D a t e : 

### 1211 5 /201 5 SU BJ EC T : U ni co n azo le-P. Human Health Assessment Seeping Doc um e nt i n S uppo r t of Registratio n Rev iew

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### IV) Pe s ticid e Re - Evaluation Di visio n (7508 P) Office of Pes ticid e Pr og ram s Attac hed is th e He a lth Effec t s Di v is io n 's ( HE D ) human hea lth ris k a ssess me nt seep in g d oc ume nt for u ni con azo le- P to s upport reg ist ration rev iew.

P age 1 

### of 23Executive Summary The H ealth Eff ect s Di v i s io n ( H EO ) uni co n azo le-P Regi st r a ti o n Re vi ew T ea m ha s ev alu a t e d th e databa se and the m ost rece nt human he alth ri s k a ssess m e nt for unicon azo le -P
. H E D p e rf o rm ed this eva lu a t ion in order to d ete rmin e th e scope of wo rk n ecessa ry to s upport the estab li s he d tolerances and exi s tin g reg i stra ti o n s during r eg i strat io n rev iew. T he pri mar y so ur ce of information f o r thi s eva lu a tion was th e most recent hum a n health ri sk assess m e nt ( 0 3 46558 ; E. Sco ll o n ; 3/ 3 1 / 2 008). U ni co nazo le , 

### (E) - (RS)- 1- ( 4-ch lo ro ph e ny l) -4 ,4 -dim e th y l- 2

- ( lf/-1 , 2,4 -tri azo l-1- y l)pe nt-l -en - 3

- o l , i s a tri azo le Group 3 fun g ic ide a nd plant g rowt h reg ulato r. The reso l ved S- i so m e r , identifi e d as unicona zo le -P , i s th e active pe st ic id al ingr edie nt a nd is th e ac t ive in g red ient in reg i s tered e nd-u se product s . Th e technica luni conazole-P prod u ct co nt ains abo ut 80% of th e S- i so m e r and 20% of the R -isome r . U ni co nazo le -P reduces plant height by redu c ing int e rn ode e longatio n thro u g h inhibiti o n of g ibb e re llin biosynthesis. Uni co nazo le- P i s reg i stered for u se in g ree nh o u ses o n ornamental p lant s a nd f ruiting vege t ab les (C rop Gro up 8) tran sp la nt s , includin g eggp lant , g roundcherry , p ep ino, p e pper , to m at ill o , and to m a to. U nicona zo le-P i s formulat ed as a 0.055% e mul s ifiabl e co n ce ntr ate. T he pr o duct i s speci fi e d fo r u se in co mm erc ia l gree nh o u ses , la thh o u ses , a nd s h adehouses as a foliar s pray o r g ro und-direct ed app li cation s u si n g handh e ld e quipm e nt. Th e t ox icolo gy d a t abase for uni co na zo le- P i s co mpl e te and n o ad diti o n a l toxi c ity s tudie s are requir ed
. H E D ' s Hazard a nd Sc ie nc e Poli cy C oun c il ( H AS PO C) deter min ed that a s ubchronic inhal a tion s tud y, acute ne uroto x ic ity battery, and s ubchro nic ne uroto x icity battery are n o t r eq uir ed f o r un iconazo le- P (U. H ab i ba ; T X R # 00572 1 2; 10 / 2 0/ 2 015 ). Pre v io u s ly , a n ac ut e di e t a ry ri s k assess m e nt was co ndu c ted for th e fe m a les 1 3-49 subpop ul a ti o n o nl y; h oweve r , fu rth e r rev iew of the toxic ity d a t a bas e indicat e that an acute di e t a r y ri s k assess m e nt f o r th e ge n e ra l population s hould be co ndu cted. T h e t arge t o r g an for uni co nazol c- P i s the li ve r re gard less of th e ro ute of exposure. The re was n o ev id e n ce of quantitative o r qualitative s u scept ibility in th e dev e lopm e ntal ra t / rabbit s tudi es or th e r e pr od ucti ve rat toxicit y s tud y. The o nl y p o t e ntial ev i de n ce of neuro tox ic i ty was cli ni ca l s ig n s that occ urr e d at do ses hi g h e r th an th ose that ca u se d li ve r tox ic ity . Th e refor e , ba se d on the co mpl ete ness of the dat abase , th e lack of s u sce ptibilit y , th e lack of concern fo r p o t e nti a l deve lo pme ntal ne urotoxi ci t y, and th e protecti ve ass umpti o n s u se d in the expos ure assess m e nt , the requ ir ed I Ox Food Qua lit y Pr o t

ec tion Ac t (FQ PA ) Safety Facto r i s reduced t o I x. The r es idu e c hemi stry d a tabase for unicona zo l e- P i s co mpl ete. Th e m e t ab o li s m of uni co n azo lep in c rops is adequate ly under s too d. T her e are n o sig ni ficant li ves tock feedstuffs assoc ia te d wi th the u se on fruitin g vege ta bl es (c rop g r o up 8). Ther e fore , n o liv es tock m e tabolism data , e n fo rce m e nt meth o d s, s to rag e s t ability data , n or feed in g st udi es w er e sub mitted. A dequ a t e e nf o rce m e nt meth ods are availa bl e for dete rminin g residu es in fr uitin g vegetable co mm o dit ies. T he to le ran ce exp ress io n (as s t ated in 40CF R 

### § 18 0.643[a]) i s n ot in accordance w ith cunent g uidan ce, as it do es not co ntain the a ppr op ri a te cove r age a nd co mpli a n ce s t a t e m e nt s ; it s h o uld be re v i se d durin g registration re v iew to co mpl y w i th H E D 's interim gu idance o n tolerance e xpr ess io n s (S
. Knizner , 5/ 27/ 2009). Ther e a re n o Codex m aximum res idu e limit s (MRLs)
P age 2 of 23es t ab li shed for uniconazole. Therefore , th ere are no h a rmoni za tion i ss u es w ith regard to Codex. The US tolerance in crop group 8 (0.0 l ppm) i s harm o nized w ith the Ca n ad ia n MRL in th e tomato s ub g roup 8-09A (0.0 1 m g/ kg). HED w ill co ndu c t a n ew dietary ri s k assess m e nt dur i n g re g i s trat ion review , to i n corporate a new acute endpoint and point of dep artu re for th e ge ner a l US p op u la tion
. Any updated assessme nt wi ll include the E nvironmental Fate and Effec t s Di vis io n (E F E D ) revised est imat e d drin k in g water concentrations (E DWCs ), if applicable. Th ere are no residential u ses currently registered for unicona zo le-P ; therefore, a quantitati ve r es id e nti a l expos u re/ ri s k assess m e nt will not b e n ee d ed to s upport Registration R ev iew . Based on th e currently registe red us e pattern ofu ni co n azo le-P ( i. e., co mm ercial g reenhouses, lat hh o u ses and s h a dehou ses), the Agency is n o t ex pect ing res ide n t ia l expos ure from spray drift. Th e need for a vo latili zat io n ri sk assessme nt fo r uniconazo le may be exam ined during Registration Review. Th e occupationa l ex p osure database is adequate to support th e registration rev ie w process fo r uni co nazo le- P. Th e mo s t rece nt occupational handle r a nd p os t-app l ication ex posur e assess m ents are not reflective of current exposure policies , but did not id e ntify ri s ks of concern. Durin g r egis trat ion review, updated occupatio n a l handl e r and post-application exposure assessments will be co nduct ed to re fl ec t a ll the reg i s te red u ses u s i ng current occupational exposure policies. Intro du c tio n U nicona zo le, (£)-( RS)-1-(4-chlorophenyl)-4 ,4 -dimethyl-2-( I H-l ,2,4-t ria zo l-1- y l) p e nt-l- e n- 3 -ol , i s a triazo le Group 3 fungicide a nd plant g rowth reg ul ator. Th e reso l ve d S-isomer , id e nt i fied as uniconazole-P , i s the active pestic id a l in gredi e nt and is the ac ti ve in gredient in r eg i s te red end- u se products. T h e tec hnical unicona zo le-P product contains about 80% o f the S -i so m e r and 2 0 % of th e R-i so m er. H E D eva luated the m os t r ece nt human h ea lth ri sk assessment f or uniconazole-P in association w ith updates to it s toxicity , exposu re, and u sage dat abases to determine if suffic ient data a re avai lab l e, a nd i f further upd ates are n eede d , t o s upport reg i strat i on re v iew. The mo s t recent hum a n h ea lth ri sk assessment was p erfo rm ed in 2008 when H ED eva lu ate d a requ est for a n ew u se on Fruiting Vegetab les C rop Group 8 (Exce pt Cuc urbit s) ( D 346558; E. Sco ll o n ; 3 / 3112008). Tol e rance s for un ico n azo le -P are estab l ished in 40 CFR 

### § 180.643. In fru itin g vegetables, th e tolerance is estab li s h ed, in term s of uni co nazole -P , it s R -enantiom e r and it s Z -isome r , at 0.01 ppm. Th e to leran ces we re se t based on th e LOQ o f the detection m eth o d s in ce there we re no quantifiable residues in peppers g rown fro m trea ted transplants. The structu re, th e c h em ica l nam es, and oth er identifiers can be fo und in the c h emica l identity table in A tt ac hm e nt l.
H aza rd ld e n tifi ca tion ffox icol ogy
Pa ge 3 of23Un ico n azo le-P is a plant g rowth regulator and re du ces plant height by re ducing int e rn o d e e lo n gati o n thro u g h inhibiti o n of g ibb e r e llin biosynthesis. Th e to x icol og ical m o d e of action in
m am m a l s is unknown. The toxicolog y database fo r uni co n azole -P i s comp le t e and n o add iti o n a l toxicity s tudi es are req uired
. l-IED 's H AS PO C dete rmin e d th a t a s ubchroni c inhalati o n study, acute ne urotoxicity batte ry , and subchronic n e ur otoxic ity battery are not requir ed for uniconazole-P (U. l-l abiba; 

### TXR#0057212; 10 /2 0 / 2015). T he t arge t organ f o r unic o naz o le- P i s the live r regar dl ess of the route of ex p os ure ; li ve r ef fect s were ob served fo ll owi n g o ral , dermal , and inhalation (ac ute o nly) exposure. The effects observed were primaril y in c rease d li ver weights , e lev a te d li ve r enzymes (aspa rtat e aminotran s fera se), an d hi s topatholo g ical changes (vac uolati o n and hypertroph y). Effec t s o n th e li ve r were see n fo ll ow in g eve n a s in g le exposure ; increased li ve r weight a nd cyto pl as mi c vacuo lat ion were observed at sac rifice (2 weeks post d ose) in the ac ute lethality studies co ndu cted by b o th o r a l and inhal a tion ex p os ur e. Th e re app ea re d to b e progress ion of the li ve r toxicity as effects were seen at lower d oses as the duration of ex p osure increa se d. Th e re was no ev id e n ce of quantitati ve o r qualitati ve susceptib ili ty in the deve lopmental ra t/ r abbit stud ies o r the rep rodu cti ve rat tox icity s tud y. Uni co n azo le-P was clas s ifi e d as a Group C che mi ca l ; Po ss ibl e Huma n Carc in oge n , ba se d on the occurrence o f li ve r tum o r s in male mice ; th e re wa s no ev id ence of carc in ogeni c ity in female mice o r in m a le and female rats. The re was no concern for mutagenicity. Th e chr o ni c Refe re nce Do se wo uld a dequatel y acco unt for a ll
c hro nic e ffect s includin g carc in oge ni c ity . In ac ut e leth a li ty s tudie s , unic onazo le-P h as low or minimal tox i c ity via the dermal ( To x ic ity Category III ) an d inh a latio n ( T ox icity Category Ill ) routes of expos ure ; howeve r , it h as moderate oral toxicity ( Toxicity Ca tegory II ). I t i s minim a ll y irritatin g to th e eye (Tox ic ity Cat ego ry Ill ) and non-irritating t o the skin (Tox ic ity Category IV ). It is n o t a d e rm al se n si tizer.
In th e most rece nt risk assessme nt , th e required lOx FQ PA Safe ty Factor was re du ced to lx b ased on: I ) the lack of in c rease d pre- and post-natal s u sceptibilit y of ra t s and rabbit s to 

### in ute ro and / o r post-natal expos ure in th e d eve lop m e nt a l a nd r e productive toxicit y s tu dies; 2) th e re is no frank evidence of ne urot ox icity in th e database (a ll clini ca l s ig n s that co uld b e rel a te d to a ne ur o toxic effect w ere see n at hi g h doses above tho se that caused li ve r toxicit y) and a developmental n e urotox ic i ty s tud y i s not r eq uire d ; and 3) th e risk assess m e nt doe s not un de re s tim ate ex po s ure b ecau se the d ietary assess m ent i s ba se d on protec ti ve assumptions suc h
as to lera nce -l eve l res idu es in f oo d s a nd upp e r-b o und modeled es timates of res idu es in drinking water. In the previou s risk assessme nt , a n acute d ietary endpo int for the ge neral populati on was not id e ntifi ed du e t o th e lack of an id e ntifi able e ffect following a s in g le ex p os ure. H oweve r , uni co n azo le -P did res ult in non-lethal toxici ty (dec rea sed spontaneo u s acti v it y and urinary inco nt in e nc e) in th e ac ut e le th a li ty stud ies. Therefore , an ac ut e di etary e ndp o int w ill b e c ho se n fo r uniconazo le- P durin g regi s tration review ba sed o n th e acu t e lethality studies; no further d a ta
Pa ge 4 of23are r eq uired. All other conclusions from the p r evious ri s k assessment are not expected to change during regist ration revi ew. The toxicol og ical e ndp oints a nd doses used in the mo st recent human health risk assessment are summa rized in Attachment 2. T he toxicity profile of uni conazo le- P is s ummarized in Attachment 3. Conclusions for Hazard I dent i fication/Toxicology The toxicity database is co mpl ete for the purpose of re gis tration review, and is appropriate for assessment of potential carci n ogenic, mutagenic , developmental , a nd reproduct ive effects
. The FQPA Safe ty Factor was red u ced to I x based on a numb er of factors including the lack of suscept ibility in deve lop ment a l and reprod uction stud ie s in rats and rabbits , th e lack of frank evidence for neurotoxicity, and the protective assumptions used in the exposure assessments. No new toxic i ty data are req uired. H owever , durin g registration review , HED w ill co n side r th e approp ri ateness of the ex i sting e ndpoint s based on current policies and ri sk assessment methodologies , including choosing an acute dietary endpoint and POD for the gene ra l US population from the currentl y availab le acute studies
. R es idue Chemistry The metabolism of uni conazo le-P in crops is adequatel y understood. Metabolites of uniconazole-P include I ,2, 4-triazo le, triazolylalanine, triazolyacetic acid , a nd tria zoly l pyruvic acid. HED conc lud ed that the tox icologica l effects resulting from exposu re to 1,2,4-tr i azo le, triazolylalanine , triazo lyacetic acid, and triazo ly lpyruvic acid are different f rom t hat res ulting from exposu re to uniconazole-P and are add re ssed as a separate aggregate ri sk assessment (0426493, 

### T. Morton , 4 / 9 / 20 1 5). Li vestock m etabo li sm s tudie s hav e n ot bee n cond u cted, as there a re no sign ificant feed items assoc iated w ith fruiting vegetables. HED concluded that the residues of concern in plant commodities (for tolerance express ion a nd risk assessment pu rposes) are defined as the parent co m pound, uni co nazol e -P (the resolved S-enantiomer , whic h i s th e pesticidal active e nanti omer), along w ith its R- enant iome r and the Z -i somer. Th e r esidues of concern in drinking water (for risk assessment) are uniconazole-P and the R-enanti omer. The es t abl i shed tolerance for uni conazole in fruiting vege ta ble s g roup 8 is su pp or t ed by adequate data. Adequate analytical methods exist for data collection and to lerance e nforc e m e nt in pl a nt commoditi es. The tolerance expression for uniconazole-P (cited in 40CFR 

### § 180. 643[a]) i s not in accordance w ith c urrent g uidance as it doe s not contain th e appropriate coverage and compliance s tatem en ts. It should be revised during registration review to co mpl y with HED 's interim guidance on tolerance express ion s. The to le r ance expression for uniconazole in 40CFR 

### § 180 .643 [a] s h o uld be revised to s tate: Tolerances are estab li s h ed for residues of the fungicide/ plant growth regulator un iconazole- P , includin g its metabolites a nd degradates , in or on th e commodities li s ted in the table below. Comp lian ce w ith th e tolerance leve l s spec ifi ed below is to be detennined by m eas urin g only uni co nazole-P 

### [(E)- (S)- 1- ( 4-chlo rophenyl)-4 , 4-d im e th y l- 2-(1 H- 1,2,4- tri azol-1-y l )penl-1-en-3-ol), its R-enantiomer and its Z-isomer. Page 5 of 23There are n o Codex MRLs estab lished for uniconaz ole
. T he refore, there are no harmoni zat ion is s ues w ith regard to Codex. T h e US tolerance in c r op g roup 8 (0.0 I ppm) i s h a rm o ni zed w ith th e Canadian MRL in th e t omat o s ub grou p 8-09A (0.0 I mg/kg). Conc lu s io ns for Residue C h emistry The r es idu e c h e mistry databa se fo r uniconazole-P is adequate to s upp ort c urre nt Registration R ev iew data requirements. Adequate metabolism (crops , li vestock, and rotat ional crops), sto ra ge s tab ility, magnitude of the residue , and proc ess ing data are ava il able to s u pport th e reg i s te red uses. Adequate methods are available for enfo rcement of the current ly establ i shed tole rances. Dietary Expos ure The Envi ronmenta l Fate and Effec t s Division (E FED ) is cond u c tin g a new dr i nking water assessment for unicona zo le- P , in order to account for new m odel in g techniques intr od u ced s in ce th e previous ri s k assessment. This n ew d ri nking wa ter assessment will include the current res idues of co n ce rn (u ni co n azo le -P , it s R-enantiomer and th e Z -i somer). H ED wi ll co nd uct a n ew dietary risk assessment during re g i strati on review , to incorporate a n ew acute end point and po int of departu re fo r the general US p opulat io n. Any updat ed assessment will include th e Env ir onmental Fate and Effects Divi s ion (E F E D) revi se d est imated drinking water co n cen tratio n s (E D WCs) , if applicab le.; This updated dietary ex po su re assessment would includ e updated co n s umption information and th e la test versio n of th e dietary model. In the mo s t rec e nt human health risk assessmen t (D346558; E. Scollon; 3 / 3 1 / 2008) , there were no acute , c hronic o r cancer dietary (food+ water) ri s k estimates of concern. The die t ary (foo d + water) est imate s serve as the aggregate risk es timat es. Conclusions for D ietary Ex p osure H E D wi ll conduct a new uniconazo le- P dietary risk assessment durin g re g i s trati o n r eview using any rev i se d EDWCs provided by EFED and in corporatin g changes in endpoi n t se l ectio n , particularly for ac ut e d ietary r isk assessment. Re s id e ntial Exposur e The re gistered uses for uniconazole-P are not app l ied by h omeowne r s to residential or r ec reat iona l sett in gs and a r e not ex pect e d to res ult in res id e ntial exposur e. The refore, a quantitative residential ex posure assessment ha s not been conducted and w ill n ot be nec essa ry for Re gis tration R ev ie w. Spray Drift Res identi a l expos ures resu lting from off

- site transp o rt (e.g., sp ray d ri ft or vola tili zat ion ) cou ld conceivably occur as a result of app li cations of unic o nazole-P. Ho wever, due to th e currently r eg ister e d use-pattern a nd application se tting s of uni co nazo le- P ( i. e., commercial g reenhou ses,
P age 6 of 23lathhouses and shade hou ses), in direct exposure from spray drift is expected to be negligible. Therefore, a quantitative sp ra y drift assessment i s not nec ess ar y for Regis tration Rev iew. The need for a volatilization risk ass ess ment for uniconazole-P may be examined during Registration Review. Co nclusions for R es identi al Exposure There are no residential u ses currently registered for unic onazo le- P; therefore , a quantitative residential expos ure/r i sk assessment i s not n ecessary during Registration Rev iew; expos ur e from drift i s not expected, but HED may consider w heth er a vo latilizati on risk assessment w ill be needed for uni co na zo le-P dur in g regi s tration r ev iew . 

### Agg r ega te Ri s k Assessme nt The most recent agg r egate ri sk assessme nt was perfonned in conjunction w i th the 2008 human healt h ri sk assessmen t. There arc no re s identi a l use s for uniconazo le-P. As a result , aggregate ex posure wa s comprised of exposures that occur thro ugh foo d and drinking water only and th e refo re, were equivalent to the ac ut e and chro ni c dietary ri sk assessments. As indi cated earli er , ac ute and chronic dietary risks we re below H ED 's level of co nce rn for the ge ne ra l U
. S
. populat ion and aJ I population subg roup s. Ap pli cat ion of uni co n azo le- P a lso results in ex po s ure to 1,2, 4-tri azo l e, triazolylalanine, triazo lyacetic acid , and triazolylpyruvic acid. These compounds are considered to be toxicologica ll y different f r o m uni co na zo le-P
. HED recent ly conducted a n aggregate risk assessment f o r these co mp o und s w ith the resu ltin g exposure estimates less th a n HED 's level of concern {0426493 , 

### T. Morton , 4/ 9 /20 1 5). Co nclu sio n s for Aggregate Assessment The uniconazo le-P ac ut e and chron ic dietary risk es timat es were all below H ED's l eve l of co ncern. At th e time of reg i stra tion review, HED w ill conduct a n ew aggrega t e ri sk assess m e nt that will be based o n updated to po int s of departure and exposure estimates from food and drinking water. 

### Occupational Exposure Uniconazole-P is fo r mulated as a 0.055% (ofu ni co n azo l e- P) emulsifiable concentrate. Th e enduse product is spec ifi ca ll y label ed for use in com m ercial gree nh ouses , lathh o u ses, a nd s hadeh o uses as a foliar sp ray or gro un d-direc t ed a ppli cat io n s using h andheld e quipm e nt. App li ca tion through an y type of irrigation system i s prohibited. As a res ult of the reg istered u ses, there is a po t ential for short- and intermediate- term occupatio nal exposure associated w ith handler activiti es ( mixin g, loadin g, and applying) as well as w ith post-app li cation activities ( i. e., r e-e ntering treated a reas). Long-term exposure is n ot expec ted for the regis te red use pattern. The personal protective equ ipm e nt ( PP E) li sted on th e reg i s t e r

ed label includ es : ba se lin e clothin g ( i.e. , lo ng-sleeved shirt a nd lo n g pants , shoes a nd socks), chem ical -r esista nt g loves and n o re s pirator. The Re s tri cted Entry [nt erval 

### (RE I) on the registered lab e l is 1 2 hours. P age 7 of23Occupational Handler s The previous exposure and risk assessment eva luated a numb e r of occ up at ion a l handler sce nario s that re pre se nted the m ajor uniconazole-P sho rt- and intermediate-term occupati onal handle r expos ure s based o n applic a tion e quipm e nt and formulation t ype ( 0 34 7096 ; S. Wan g; 03112/ 2008). H ED u se d s urr ogate data from th e PH E D Ve rs io n 1.1 ( PH E D Su rrogate Exposu re Guide , 8/ 98) to assess expos ures. D efault s estab l i s hed by th e HED Science Adv i sory Co un c i l for Expo s ure were u se d for amounts treate d p e r day and body weight. Occ upati o n a l h andle r scenari os resu lted in risk esti m ates that we re not of conce rn at baseline / labe led leve l cl o thin g ( i.e. , lo ng- s leev ed shi r t and lon g pant s , shoes and socks) and chemical-resistant gloves.
In addition , HED previous ly assessed s hort- and inte rm ed iate-te m1 inhalation ex po s ur es for occ up ation al handlers. The risk es tim ates were not of concern for a ll registered uses. In
co njun c ti o n w ith det e rminin g d a ta n ee d s durin g re g i s tration r ev iew , unicona zo le-P was revi ewe d by th e HED HA S PO C to evalu a te th e ne ed for a route- specific inh a lation study because th e previous assess m e nt was co ndu c t ed using data from an o ral s tud y (0347096; S. W a ng ; 0 3/ 12/2 008). Re v ised inhalation ri sk estimates were ca lcu lated for occ up ati o nal h a ndl ers u s in g cu rrent policies and exposure ass um pti ons. Sho rt- and intermediate-term occ upati ona l h andle r inhal ation MOEs ran ge d from 34,000 to 40,000 ,000 ( LO C= 1 00) and ar e not of concern a t baseline atlire w ith no respi rator (U. H ab i ba; T XR# 0057212; 10 / 20/2015)
. Since new exposure data (i.e., updated unit ex p os ure va lu es for occ upational handl e r s) are available to assess ex po s ure to occ upati o nal handl ers, H E D w ill r eeva lu ate the occup atio n a l handler assessme nt for unic onazo le- P to address upd a t es to l-IED 's expos ure policies , includin g updat es to default ex po s ure data u se d for handler sce n ario s a nd ass umption s for body we ights
. Occupational P os t-applicati o n The previous ri sk assessment evaluated a number of occupational post-application sce n ario s that
rep rese nte d the maj o r uniconazole-P occupa ti o n a l post-application exposu re sce n a ri os based on th e reg i stered u ses. HED ha s determined that there are potent ia l d e nnal ex p os ures to pe rso n s e nterin g trea ted s ites (e.g., harvesters) after application. So urces of ge ne ri c p os t-applicati on data, used as su rrogate data in the absence of c hemica l- spec ifi c data, are derived from Ag ri c ultural Reentry Task Force (ARTF) exposure monitorin g studi es . HED u sed s t andard va lu es recommended for use in predicting post
- ap pli cation exposure in the 2008 ri sk assess m e nt , known
as " transfer coe ffici e nt s" o r T Cs
. The TC values are presented in the ExpoSAC Po li cy 3 which, alo n g w ith additional inf o rn1ati on about the A R T F data, ca n be found at the Agency website 1 • The 2008 ri sk assessment indic ate d that occ up ational po s t-applicati o n sce narios re s ult ed in ri s k
es tim ates n o t of co nce rn for wo rker s conducting ac ti v iti es o n treated areas. In addition, th e REI s pecifi e d on th e registered label i s based o n th e ac ut e tox ic ity of uniconazole-P. 

### It i s classified as Tox ic i ty Catego ry III v ia the dermal route a nd Toxicity C ate go ry IV for s kin irrit ation potential. 

### It is not a s kin se nsiti zer. S h ort- a nd intermediate-term

1 A vai lab le at: http: // www2.epa.gov / pesticide-scicnce-and

- assessing-pes t icide-ri s k s/ occupat ional-pestic ide-po s tapplica ti on-exposure. Pa ge 8 of 23post-applicatio n ri sk es timates we re n ot a concern o n day 0 ( i .e . , 1 2 hours fo ll ow in g app li ca ti o n) for all post-appl icati on act i v iti es (0347096; S. Wang; 03112 /2008). U nd e r 40 CFR 156. 208 (c) (2) (iii), a i 's clas s ifi e d as Acute III or T V for ac ute dermal , eye irrit a ti on and pri m ary sk in irrit ation are ass i gned a 12-hour REI. Therefore , the [ 1 56 sub p art K] Worker Protection Stateme n t RE I of 1 2 h ou r s appearing on th e registered label is adequate to prot ect ag r icul tura l wo rke r s f rom po s t- ap plicati o n exposu r e to uni co nazo le- P. In accordance with the updated 40 CFR Part 1 58 data requirements (2007) , one o r more Di s lodgea bl e Fo li ar Residue ( OFR) stud ies are r e quire d when a pest ic id e h as re s identia l o r occ u patio n al uses th at cou ld result in post
- ap pli cat ion derma l exposu re. Since the highest est im ated occupational post-application exposure using default DFR values for uni co n azo le- P is minim a l in co mpari so n to the leve l of concern ( i. e . , the ca lculate d MOE i s g reate r than 2 tim es higher than the leve l of co n cern , MOE = 450 compared to the LOC of I 00 using the updated science po l icies); H ED has determined that the DF R data are n ot needed. In thi s in stance , it i s unlikely th at c h e mical -spec i fic DFR dat a wou l d b e needed to furthe r r efi n e expos ur e assessments or would add apprec iably to ou r overa ll unde r stand ing of the availab ility of d i slodgeab le foliar pes ti cide residues for u n iconazole-P. T h ere are multiple potential sources of post-application inhalation exposure to i ndividua l s performing post-application ac ti v iti es in previously treated fields. Th ese potent ia l so u rces inc lude vo la ti I iza tion of pestic ides and res u s p e n s io n of du sts and/o r parti cu lates that contain pesticides. Th e Age n cy sought expert advice and i nput on i ssues related to volati li zat ion of pesticides from it s Federa l In sec ti cide, Fu n gicide , a nd Rodenticide Act Scie ntifi c Adv i sory Panel (SA P ) in D ece mb e r 2009, a nd rece ive d th e SAP's final r epo rt o n March 2 , 20 I 0 2

. The Age n cy has evaluated the SAP report and has deve loped a Volati li zation Scree n i n g Tool and a subsequent Volat ili zatio n Scree nin g Analysis 3

. During r eg i strati o n rev iew, the Age n cy wi ll utili ze this analysis t o dete rmin e if data ( i .e., flu x studi es, r o ute- spec ific inh a lation t oxico log i ca l studies) or further analys i s are required for uni conazole-P. A lth ough a quanti ta ti ve occ up at io n a l post-app li ca tion in h a lation expos ure assess m e nt was n ot previously pe r formed , an i nhalation exposure assess m en t was pe r formed for occupat io n al handlers. Handl e r ex p os ure resulting from application o f pesticides outdoors i s li ke ly to resu lt in hi g h e r ex po su re th a n post
- application expos ure . Th erefo re , it i s expec t ed that th ese handl e r inhalatio n exposure estimates wou ld be protec ti ve of most occ u patio n a l post-app l ication inhalation expos ure scenar i os. The Worker Protect i on S t an dard (W PS ) for Ag ri c ultur a l Pes ti c id es a l so co ntain s re quireme nt s fo r protecting wo rkers from inhalation expos ur es during and after greenhouse applica tions throug h the use of ventilat io n requireme n ts [ 40 C FR 170.110, (3) (Restrict i ons associated with pesticide applications)].
Co n c lu sio n s for Occupationa l Exposure a nd R i sks

2 A vai I ab le at: http ://www.cpa.gov/ scipo ly / SA P / meeting s/ 2009/ 120 I 09meeting.htm l. 3 A v ailablc at : http :// www . rc g ulation s.g ov /# !d o cketDetaii ; D = EPA- H Q -O PP- 2 0 14-0219
. P age 9 of 23Th e o c c up a tion a l ex p os ure database i s a d e qu a t e to s u p p o rt th e re g i s trati o n r ev iew pr o c ess f o r uni co nazo l e -P. T h e prev iou s a sses sm e nt addresse d th e o ccup a ti o n a l handl e r sce n ari os a nti c ipate d for a ll reg i s t e r

e d u ses. U pd ate d occ upati o n a l h a ndler and po s t- a ppli c at io n ( d e rmal ) ex p os ure assess m e nts m ay b e req uir ed und e r R eg i s trat io n R ev i ew b ase d up o n rev i s io n s t o the Age ncy 's s cenario- s p ec ific surr og ate ex po s ure data a nd a ss umption s for b o dy we i g ht s . A n y c h a n g e s re lat e d to t ox ic ol og ica l POD w ill al so b e in co rp o ra ted. Th e Agen cy ma y a l so rev i s it th e n ee d for a qu a ntit a ti ve occ up a ti o n a l p os t-appli cati o n ( i nhal a ti o n ) ex p os ure assess m e nt f o r uni c onazo le -P during R eg i s tr a ti o n R ev iew . 

### Ri s k Assessment Updates, Data Deficiencie s, and Label Revisions No d a t a d e fi c ie n c i es we re id e nti fie d fo r uni co n azol e- P
. E PA anti c ip a t es co ndu c tin g th e f o ll owi n g ri sk assess m e nt u p d a te s durin g r eg i s trati on rev iew : T ox i co logy : • H E D will c on s id e r the a ppropri a t e n ess of th e ex i s tin g e ndp o int s an d POD s base d o n c urrent p o lici es a nd ri s k a ss e ss ment m e thodol og ies; HED ex p e cts to se l ect an acute di e t a ry e n d poin t an d d ose f o r th e ge n e ra l US pop ul a ti o n. Di e tar y Ex p os ure: • A rev i se d di e tar y ex p os ure an a l ysis w ill b e re quir e d t o re fl ec t th e n ew a cute di e t a r y e ndpoint a nd do se for ri s k a ssess m e nt , a s well as pote ntial r e v i se d dr inkin g wat e r es tim a tes. O cc up a ti o n a l / R es identi a l Ex p os ure: • H E D anti c ip ates co ndu c tin g a rev i se d occ up a ti o nal ex p os ure assess m e nt t o re fl ec t th e u se of th e m os t rec e nt handl e r e xp os ure data and updat e d body w e i g ht s. 

### Public He a lth and Pesticide E pidemiology Data Fo r thi s evalu a ti o n , th e Age n cy co n s ult e d th e O PP In c id e nt D a t a Sys t e m (I D S) , th e Ce nt e r s fo r Di se ase C ontrol and Pr eve nti o n / Nati o nalln s titute for Occup a tion a l S afet y and H e alth (C D CIN IOS H ) Se ntin e l Eve nt No tifi cat io n Sys te m f o r Occu pati o n a l Ri s k

- P es ti c id es ( S ENS OR) , and th e Na tional Pes ticid e Inf o rmati o n C ent e r (N P I C) datab ases f o r p es ti c id e incid e nt d a t a o n th e a cti ve in g re d ie nt uni co n azo l e- P ( D 42 88 99; S
. R eco re; 9 11 2 115 )
. U nicona zo le- P i s n o t in cl ud e d in th e Ag ricultu ra l H ea lth S tu dy (AHS); th e refo re , th a t stu dy d oes n ot p rov id e informati o n for thi s do c ument. T h e r e w e r e no in c id e nt cases r e p o rt e d , invo lv in g uni co nazo le -P , t o e ith e r I D S or S ENS OR

P es ti c id es . Th e r e d oes n o t app ear t o b e a c o n ce rn at thi s tim e that would w a nant f urthe r in ves ti gati o n . T h e Age n cy w ill co ntinu e t o m o n it o r th e in c i de nt in fo rm a ti o n and i f a co n ce rn i s tri gg er e d , additional an a lys is will b e includ ed in th e ri s k a ssess m e nt. 

### Tolerance Assess m e nt and Int e rnational H a rmoni zation

Pa ge 10 of23Tolerances for uni conazo le are estab li s hed under 40CFR 

### § 180. 643 for r es idu es re su ltin g fro m applications of the fungicide/ pl a nt growth r eg ulator to frui tin g vegetab les . The tol e ranc e ex pression is not in accordance w ith c urrent guida n ce, as it d oes n o t co ntain the appropriate cove rage a n d co mplianc e s tatem e nts. 

### It shou ld b e rev i se d durin g reg i s tration review to comply w ith H ED 's interim gui d ance on tolerance expressio n s, as stated a b ove in th e residue chemistry se ction. T her e are n o Codex MRLs established for res idu es ofuniconazole at thi s time. A Ca nadi a n MRL ex i sts for unic o n azo le in the tom a to s ub gro up 8

- 09A ; the residue d efi nition s are n o t the sa me for the US and Canada. The US tole ra nce in c rop g ro up 8 (0.01 ppm) i s ham1 o nized with th e Canadian MRL in th e tom a to s ub g roup 8-09A (0.0 1 m g/kg). An I nternati o n a l R es idu e Limit Statu s s heet is attac hed to this document as Attachme nt 4. There are no pending requests for the establishmen t of n ew to lerances for uniconazole. Env ironme nt a l Ju s tice Po tenti a l areas of e n v ir o nment al j us t ic e concerns , to the extent possib le, w ill be considered in Registration Review , in accorda n ce w ith U.S. Executive O rder 1 2898, " Fed e ral Actions to Address Environmental Ju stic e in Minority Populati o n s a nd Low- In co m e P opu lati o n s," ( http :// www. h ss.ene rgy .gov /nu c lear safe ty / e n v / gu idance / justice/eo 12898.pd 

### 1). Th e OPP t y picall y c o n s id e r s the hi g hest potent ia l exposures from the le ga l us e of a p es ticid e when co ndu cti n g human-health ri sk assessments, including , but not limited to , people who obta in drinking water from so urces n ea r agr ic ultural areas, the va ri ab ility of di e ts w ithin th e U.S ., and peop le w h o might be exposed w hen h arves tin g crops. S h ou ld these hi g hest exposures in d icat e potential ri sks of co ncern , OPP further re fin es the ri sk assessments to e n s ur e th at th e risk es timat es are based o n th e best ava il ab le information. C umul at ive Ri s k Assessments Sect ion 408(b)(2)(D)(v) of the FFDCA requ ir es that , when considering w h e th er to estab li s h , modify , or revoke a tolerance , the Age n cy consi d er "ava il able in fo rm a ti o n co nce rnin g th e cumulative effec t s" of a particu la r pe s ticide' s residu es and "othe r s ub sta nce s that ha ve a co mm o n mechanism oftox icity
. " Uniconazole i s a member of th e triazole-containing c la ss of pesticides. A lth oug h these co nazo les ac t s imil a rl y in plants by inhibitin g e rgos te rol biosynthesis, there i s n ot n ecessaril y a re lat ions hip between th ei r pesticidal ac ti v ity an d their m ec hani sm of toxicity in mammals. Structu r al s imil ari ti es do n ot const itute a common m ec h an i s m of toxicity. Ev iden ce i s n eeded to es tabli s h that the c he mi cal s operate by th e same, or esse nti a ll y th e sa m e, seq u e nc e of m ajor bioc hemica l eve nts (E P A, 2002). In conazo les, h oweve r , a var iab l e pattern of to xico logica l res pon ses i s found. R esponses includ e hep a totoxicity and hepatocarcin oge ni c ity in mic e, th y ro id tumor s in rat s, and deve lopme nt al, reproductive , and n euro log ica l effec t s in rodent s . Furth e rmore, the conazo les produce a diverse ran ge of biochemi ca l events includin g a lte r e d choleste rol leve ls, s tr ess r esponses, and altered DNA methylation. 

### It i s not clearly under s tood whethe r these biochemical eve nt s are directly connected t o their toxic o logical outcomes. Thu s, Pa ge 11 of 23there i s current l y no ev id e n ce to indi cate that conazoles share common mechanisms of toxicity , and EPA is not following a cumulative risk approach ba sed on a co mm on m ec hani s m of toxicity for the conazo les. For in formation re garding EPA 's procedures for cumulati n g effects from
s ub sta nce s found to ha ve a common mech a ni s m of toxicity , see E PA 's website at http: // www.epa.gov / pesticides/ cumu lative. 

### Human Studie s The 2008 ri sk assessment relied in part on data from studies in whic h adult human s ubjects were intentionally exposed to a pesticide or other chemica l. These data , which include s tudies from Pesticide Handler Exposure D a t abase (P H ED) 1.1 a nd the Agricultural Reentry Task Force (ARTF) database , are : (I) subject to ethics review p ur suan t to 40 CFR 26, (2) hav e received that re view , and (3) are compliant with app licabl e ethi cs requirements. For certain s tudi es, the ethic s review may have included review b y the Human Studies Review Board. D esc riptions of data so urces, as well as guida n ce on their use, can be found at the Age n cy website". 

### References Author Barcode Date Title S. Wang 034 7096 3 / 12/ 2008 Occupationa l and Resid e ntial Exposure / Risk A ssess ment of Uniconazole for New Use on Fruiting Vegetables (Peppe r , Tomato , Eggplan t , etc.). E.Sc o ll o n 0346558 3 / 31/2008 Uniconazolc-P Human Health Ri sk Assessment for Prop osed Uses on Fruiting Vegetables (Excep t Cucurbits) , Cro p Gro up 8 U. H abiba TX R # 0057212 10 / 20 /2015 Uniconazole: Summary of Hazard and Science Policy Counci l ( HASPO C) Meeting of Jul y 23, 20 15: R ecomm enda tion on the R

equ ir eme nt for a S ub ch ronic Inh a lati o n Study , Acute Neurotoxicity Battery and Subchronic Neurotoxicity Battery
. S. Recore 0428899 9112 / 1 5 Uniconazole: Tier I (Scoping) Review of Human Incid e nts and Ep idemiology T. Morto n 0426493 4/09/ 1 5 Common Triazolc Mctabolih: s: U pdated Aggregate Human Health Ri sk Assessment to Address The New Sec tion 3 Registrations For Usc of Propiconazole on Tea, Dill. Mu s tard Greens. Radish. and Watercress: Usc of Difenoconazole on Globe Artichoke. Gin se n g and Greenhouse Grown Cucumbers and Conversion of the Estab li s hed Foliar Uses/Tolerances for Stone Fruit and Tr ee Nut Crop Groups to Fruit. Sto ne . Group 12-12 and the Nut, Tree. Group 14-1 2.; and Use of f'lutriafol on H ops.


### Attachments At tachment I. Chemical I dentity Table for Uniconazole Attachment 2. Un iconazole-P Endpoint Selection Tables Attachment 3. Summary of Acute, Subchronic and Chronic Toxicity Profile , Toxicological Doses for Un ico nazo le-P for Use in Hum an H ea lth Ri s k Assessments

4 Ava iI able at: http: // www2.epa.gov / pesticide-scicnce-and-assessing-pest icide

- risk s / occupa tional-p es t icidehand ler-ex pos ure-data and http :// www2. epa. go v / pe s t ic ide-sc ie nee-and -asse ss ing -pe s ticide-ri s ks /occupation a)- p es ti cide-pos t-applic a tion-exp osu re . Page 

### 12 of 23Attachment 4
. Internation al Res idue Limit S ta tu s A tta c hm ent 

### 5. S ummar y of End-Us e Prod u cts Co ntainin g Unico n azo l e -P.



### Pa ge 13 of 23

### A tt ac hm e nt 

### 1. U nic o nazo le C he mical id e nti ty . Tab l e AL I. Uni co n azo l e No m enc l at ur e . C h e mi ca l str uc tur e Cl

Common na m e Co mp a n y expe rim e ntal nam e IUPA C name CAS na me
CAS r eg istry numb er End-u se product (E P) Uniconazo l e ( unreso l ved mixture) Non e (£)

- (RS) -1-(4-chlorophenyl ) -4,4-dimeth y l2-( I H- 1 ,2,4 -triazol- 1 -yl)pent-l-cn-3-ol CP£) -P-[(4-chlo r ophenyl)me th y l e n

e]-a- ( I , I

- dimc th y l ethy l ) -1 H-1 , 2 ,4-triazo l e-1- eth ano l 83657-22- 1 None

T a bl e A l. 2. P hysicoc h e mi ca l Pr op e r ties o f Uni c o nazo l e. C l

Uniconazole-P (S -isomer) XE-10 19 D (£)-(S)-1

- ( 4-chlorophen y l )-4,4

- dim eth y l

2-( I H-1 ,2,4 -tri azo l-l- yl)pcn t-1- en-3-o l (aS , p£)-p -[ (4- chlorophen y l) m eth y l en

e ]- a- ( I , 1-dimethy leth y l)-l//-l ,2, 4 -tri azo l e -1- eth ano l 836 57 -17-4 Va ri o us

Pa r a m e te r Va l ue Re f e r ence Meltin g poin t/ra nge 150°C MRID # 46424905 p H 6.54 ( I % s uspe ns ion of uni conazo l e) D

ensity 1.256 g/ mL 

## em 20 °C Wate r s olub il it y I 1.1 m g/L at 20 °C So l ven t so lubilit y Not S ubmitte d Vapor pressure 1 .0 x 1 0· 8 Pa @ 20 °C MR ID # 46424907 2.3 X I0' 8 Pa @ 25°C Di ssoc ia ti o n co ns tan t , pK
. Do es no t di ssoc iate MRID # 46424905 Octanol / wa ter partition coe ffici e nt , Log(Kow ) Log(K ow) = 3.67 @l 25°C UV / visible absorpt io n spectrum No s ignificant differences were ob se r ved between the spectra ob tain ed f o r th e acid ic , a l kaline , a nd neutra l sa mple s.



### Pag e 14 of 2 3

### Attachment 2. U nic onazo le- P Endpoi nt Se lecti o n Tables.

Tabl e A2. 1. Summary of Toxicological Do ses an d E ndp oi n ts for U ni co n azolc-P for Use in Dietary a nd NonOccupational Hum an Hea lth Risk Assessme n ts. RID , PAD , Ex p os ure/ Point of Uncerta int y/FQPA Leve l o f Study a nd Toxicologica l Eff ects Co n cern for Sce n a ri o D epa rture Sa f e ty Factors Ri s k Assess m e nt UF A= lOx Acute RID = Acute Dietary NOAEL = UF H

= IO x 0.05 mglkg/da y Pr ena tal Developmental Toxicity- rat ( F

ema l es 1 3-49 5 FQPA SF = l x LOA EL = 25 m glkg/ da y based on yea rs of age) m g!kg/ day aPAD = 0.05 incr ease d incid e nc e of 14 111 rib m

g/k glday Chronic RID = C hron i c Oral (Caps ule) Toxicity- dog NOAEL= UF , , = lO x 0.02 LOAEL = 20 m glkg/ da y base d on th e Chronic Di etary 2 UFu = l Ox m g/k glday incr ea s ed absolu te a nd re la ti ve liver ( All Population s) mglk g/ day FQPA SF= lx weigh t c hanges in males supported by cPAD = 0.02 hi s to lo g ical and e nzym e changes in th e m

glk g/ day liv er In cidental Oral NOAEL = UF A = lOx Pr ena t a l D eve l opmen t a l Toxicity- rat Short- ( 1-30 da ys ) R eside nti a l LOC and I nt er medi a te5 UF H

= lO x for MO E= 100 LOA EL 

### = 25 rn glkglda y base d on Tenn ( 1-6 month s ) m g/

k

g/

da y FQPASF = lx d ec rea s ed mat ern a l b ody weig ht ga in Dermal Short- ( 1- NOAEL = UF" = l Ox Resid e ntial LO C Subchronic D e rmal Toxicit y - rat 30 day s ) a nd 5 UFH = lO x for MOE= 100 LOAEL = 25 m glkg! da y based on Int er m ed iate-T erm mglk g! day FQPA SF = l x increa s ed live r weig ht and ( 1- 6 months )

**hi stopatholog~**  of the li ver Inh a lation Short- NOAEL = UFA= l Ox R es id e n tial LO C Pr e natal Deve lopm ental To x icit y- rat ( 1- 30 days) a nd Int enned iat e- Term 5 UFH = lO x for MOE = 10 0 LO AEL 

### = 25 mglkg/day based on ( 1-6 months) m g! k g/

day FQPA SF = lx increas ed i ncidence of 14 th rib Uni co nazol e was classified by th e HED Ca rcino ge nicit y P ee r R eview Comminee a s a Group C , Cancer (o ral , po ss ib l e hum a n carc in ogen. Th e CA RC recommended th e refe re n ce dose ( RID ) approach for risk dem1al , inhalation ) as s e ss ment and concluded that th e ch ronic RID wo uld be protective of all c hronic effec t s including carc in oge ni c it y ( TXR No.0052723). Pomt o f Departure ( POD )= A data pomt or a n estim a ted pomt th a t 1

s dcn v ed from ob se r v ed do se -re s pon s e da ta a nd used t o m a rk the b eg innin g o f ex trapo lati on t o determin e ri sk assoc iated with low e r en v iro nmentall y r e le vant human exp os ure s. NOA EL 

### = no ob served adverse eff ect level. LOAEL = lowest ob served adverse effec t level. UF = uncertainty factor. UFA= extr a p olat i on from a nim al to human (inters pccies). UF11 = potential var i ati on in sens iti vit y among members of th e hum an po pulation ( intr 8$ pec ies). U F

L= u sc of a LOAEL to ex trapolate a N OAEL
. U Fs =u se o f a s hort

- term s tudy f o r lo ng-term ri s k ass e ss m e nt. U

F

oo = t o a ccount for the ab se n ce of k ey data ( i
. e .. l ac k of a criti cal s tud y}. FQPA SF = FQPA S afet y Factor
. PAD = population adju sted do se (a = a c ute, c = chron ic). RID = reference dose. M OE= m argi n of exposu r e . LOC = l eve l of co n ce rn . N / A = not applicab l e .



### Page 1 5 of23Tab l e A2
. 2. S umm ary of Toxico l og i cal D oses a n d Endp o int s f o r U ni co n azo l e- P for Use in Occupa ti o n a l Human Hea lth Ri s k Asse s s ment s. Exp o s ur e / Point o f Unc e rt a int y Level of Co n ce rn for Ri sk S tud y a nd Toxicologica l Eff ec t s Sce n ario Departur e Facto r s A s s ess m e n t D

ermal S hort- S ubchro nic Dermal Toxicity- rat and O cc up a ti o na l Int e rm edi a t e NOAE L = 5 UF A= I Ox LOC f or MOE= L OA EL = 2 5 m glkglda y base d o n T erm (0-6 m glkgld ay UFu = IOx 1 0 0 in c rease d li ve r we ig ht and hi s to pa th o lo gy
m

o nth s) ofthe live r Inh al ati o n S hort- a nd NOAEL = 5 UF A = IO x Occ upation a l Pr e natal D e ve lopm e ntal T o xicir y - ra t Int erm edi a t e - m glkgld ay UFu = IOx L OC f o r M OE= LOAEL = 2 5 m glkg/ d ay b ase d on term (0-6 1 00 in creased in c id e n ce of 1 4'h r ib month s ) Ca n ce r (ora l, Uni co nazo l e w as c lass ifi ed by th e HE D Ca r c in oge ni c it y Pe e r R ev iew Co mmitt ee a s a Gro up C , p oss ibl e human ca r c ino ge n . T h e C PR C reco mm e n de d th e re f ere n ce dose ( R ID) ap pr oac h f o r d ermal , ri s k assess ment and conclud ed th a t th e chronic RID wo uld b e protecti ve o f all chroni c e ff e ct s inhalati o n ) in c ludin g carcino ge nici ty (TX R No. 005 2723). Pom t of Depar ture (POD)= A data pomt or an estimated pomt tha t IS dcnved from observ..:d dose

- response data and used t o m

a rk th e beg innin g o f ex trap o la ti o n t o d et e rmin e ri s k assoc i a t ed w ith l owe r e nv i ro nm e nt a ll y re l eva nt hum a n expos ures. NOAEL

= no o bse r ved a d ve rse ef f ec t leve l. LOAEL = lowes t o bse r ve d adve rse e ff ec t l eve l. U F = un ce rt a int y f ac t o r. U F A = extrapolation fro m animal t o human (interspecies). UFH = poten ti a l va r iatio n in sensi t ivi t y among members of th e h uma n pop ul a ti o n ( intraspecies). UFL = use of a LOAEL to ex trapo late a NOAEL. UFs = use of a sho n-tenn study for lo ng-tenn ris k assess ment. UFos = t o acco unt f o r th e abse nce o f k ey dat a ( i. e .. l a ck of a c riti ca l stud y). MOE= m a r

g in o f ex pos ure. LOC = level of concern. N/ 1\ "" no t a p p licab l e. 

### Attachment 3. S umm ary of Acute , Subchronic and C hroni c Toxicit y Profile , Toxi c olo g ical D os e s f o r U nic o n az ol e -P for Use in Human He alth Ri s k A ss e s sm e nt s .
Table A3.1. Ac ute Toxicity Profile

- U nic onazo l c-P. G uideline Study Ty p e MRID(s) Re s ult s Toxicity No. Cate gory 870.1100 Acut e oral

- rat 40 3 45405 LD so II 

### S-3 3 070 , Lot PY-8 4 013 , M 

## = 4 60 m g/ k g Purit y 97.2 %, E/ Z 

## = 96.2/3 .8 , RJ S 

## = 20.8/7 9.2 F 

## = 430 mg/k g 870.1 2 00 Acute derm a l

- rat 40345408 LDs o 

### > 2 000 Ill 

### S-33070 , Lot No
. PY- mg/kg 840 1 3, Puri ty 97 .2% E/ Z96. 2/3 .8 ; RJ S 

## = 20
. 8/7 9.2 870.1 3 00 Acute inhal a tion

- r a t 40 3 4 5409 LC so 

### > 2 .75 Ill 

### S

- 330 70 , Lo t PYG-8 6 04 7. m g/L Purit y 97.6 %, E2 

## = 96.9 / 3
. 1 , ES / E R 

## = 8 0.6 / 1 9 .4 870
. 2400 Acut e e ye irritation

- rabbit 40 3 45411 Min im a ll y Ill 

### S

- 3 3 0 7 0 , Lo t PY -84013 , irrit atin g Purity 97
. 2%, E / Z 

## = 96.2/3 .8 ; RJ S 

## = 20.8/79
. 2 P a g e 

### 16 of 23

### Tab l e A3.1. Ac u te Toxicity Profile- U ni co n azo l e-P. G u ide l i n e Study Ty p e MRID(s) Res ul ts Toxicity No . Category 870.2500 Acute derma l irritati o n - 40345411 Not irritating 

### IV rabbit S-33070 , Lot PY-8401 3 , Purity 97.2% , E/ Z 

### = 96.2 / 3.8 ; R/S 

### = 20.8/79.2 870.2600 Skin se n sitization

- gu in ea 40345 41 2 Not a sk in 

### NA pig se n s iti ze r S

- 3307-0, Lot PY-8401 3 , Purity 97.2%, E/ Z 

### = 96.2 / 3 .8 ; R/S 20
. 8/79.2 There are s evera l ve r sions of th e technica l g rade ac ti ve in g redie nt that we re tested i n the acut e batt ery. T h e tec lmical uni co n azo l e can co ntain va ri o u s quanti ti es of re lated i so m e r s w hich can a lte r the c h e mi s try and t ox ico l ogy of the t es t s ub s tance. T h e s tudi es li sted above that were p e rform e d with the t ec hni ca l grade active in g re dient are the s tudi es that provid e th e mo s t prote c tiv e toxicity categories.

P age 17 of23

### Tab l e A3.2. Tox i c i ty St udi es P ro fil e. G ui de li ne No . MRI D No . (year)/ R es ul ts C lass ifi ca ti on /Doses 870
. 3 100 40462605 ( 1986) NOAE L 

## = 7.5 m g/ kg/ day Subch r onic Acceptab le / g uidelin e LOAEL 

## = 73.0 mg/ kg/ day based on based on ora l toxicity 

### 0, 30, 100 , l 000, 3000 ppm c h anges in body weights , hematology , lipid (rat) 

### M: 0 , 23, 7.5, 73.0 , 228.0 metabolism and effects o n liver and th y roid. m g/kg/day F: 

### 0 , 2.4 , 8.4, 79.4 , 229.0 m g/ k g/ da y 

### 870.3150 40462606 ( 1986 ) NOAEL 

## = 20 m g/kg/day Subc hronic Acceptable / guidel in e LOAEL 

## = 80 mg/k g/ day based on in c reased oral (capsu le) 

### 0, 5, 20, 80 , 320 mg/ kg/day alka lin e phosphatas e activity (males and toxicit y (dog) in ge latin capsules females) a nd incr eased liver weights ( m ales)
. 

### 870.3100 4144240 I (1986) NOAE L 

## = 58 mg/k g/ day Subchronic Acceptable-Nong uid e lin e LOAEL 

## = 193 mglk g/day based on the body Oral (Feeding) 

### 0 , 100 , 300 , 1000 , 3000, weight cha n ges, clinical chemistry changes , Toxicit y S tud y 

### 10000 ppm hematology changes and li ver e ffects. (Mouse) M: 

### 0,20 , 58, 193,622, 5 weeks 

### 2673 m g/kg/day 

### F: 0,27 , 77,274 , 849 , 3758 mg/kg/ day 

### 870.3200 40462607 ( 1987) Syste mi c Toxicity NOAEL 

## = 5 m g/k g/day S u bchronic Acceptable / guidel in e System ic Toxicity L OAE L 

## = 25 m g/ k g/day dermal tox icit y 

### 0 , 5 ,2 5,50 , 200,500 based on increased liver weight and



### - 28 day ( rat ) m g/kg/day hi s topatholo gy of the l iv e r. Dem1al T oxicity NOAEL 

### < 5 m g/ kg/day Dermal Toxicity LOAEL 

### :S 5 mglkg/ da y based o n dermal irritation at all dose levels te s t ed
. 

### 870.3200 41162003 ( 1989) Sys t emic Toxicity NOAEL 

### 2': I 000 m g/k g/ day. Subchronic Acceptable/ guide lin e Systemic T oxicity LOAEL was not ach ieved
. de r mal toxicity 

### 0 , 100 ,5 00 , 1000 D er mal Toxicity NOAEL 

### 2: I 000 m g/kg/day.



### - 28 da ys (ra t ) mglk g/ da y Dermal Toxic it y LOAEL was not achiev e d. Formulation However , the irritation noted at all dose levels 

### 2.66% a. i
. was slight.

Page 1 8 of23

### T a b l e A3
. 2. 

### Tox i ci ty S tudi es Profil e . Guid e li n e N o. MRID N o. (ye ar)/ R es ul t s C las si fi c a t i on / Do s es 870.3200 41162002 ( 1987 ) Only a si ngle dose t es ted. Subchron ic Acceptable/guide li ne Den n al Toxicity LOAEL

**~** l 

### 000 mg/kg/ day dern1al toxicity 

### 0, 1 000 m g/kg/ da y based on acanthosis noted.



### - 28 days ( rat) No sys t e m ic toxicity was noted. Formulati on 

### 0
. 05% a.i. 

### 870. 3700 40462609 ( 1 987) Materna l Toxic ity NOAEL 

## = 5 mg/k g/ day Pren a tal 

### 42123201 ( 1991) Maternal Toxicity LOAEL 

## = 25 m g/kg/day dev e lopm e ntal Acceptable/guide !in e based o n decrease d body we i ght. toxi c ity ( r a t ) Developmental Toxicity NOAEL 

## = 5 0, 1, 5 , 25 , 50 mg/kg/day in mg/k g/ day 

### 0
. 5%CMC Developmental Tox icity LOAEL 

## = 25 m g/kg/day based on increased in c idenc e of 

### 14 1 11 r ib. 

### 870.3700 4046 26 10 ( 1987 ) Maternal Toxicity NOAEL 

## = l 

### 0 mg/k g/ day Acceptable/g uide! i ne Maternal Toxicity LOAEL 

## = 20 m g/kg/ day Pr e n ata l 

### 0 , 1 , 3, l 

### 0 , 2 0 m g/kg/ day in based on statistica ll y significant r e duced food developm e nta l 

### 0.5%CMC consumption and marg i nally reduced body tox ic ity we ight ga in s . (rabbit) Developmenta l Toxicity NOAEL

**~** 

### 20 mg/kg/day (HDT)
. Deve lopme n tal Tox icity LOAEL was no t ac h ie ved.

P age 

### 19 of 23

### Table A3.2. 

### Toxicity Stud i es P rofile. Guideline No. MRID No. (year)/ Re s ults C l ass ification /Do s es 870. 3 800 4116 20 04 ( 1 9 8 9) P a re nt a l Sys t e mi c T ox ic ity N O AE L 

## = 7.5 Repro du c tion Acc ept a bl e / g uid e !in e m g/kg/ day P a re nt a l S y s t e mi c Tox ic ity LO AE L 

## = 75 a nd f e rti li ty 

### 0, 15 , 150 , 15 00 p pm e ff ec t s m g/kg/ d ay b ase d o n re duc e d b o d y we ig ht a nd ( rat ) 

### 0 , 0.7 5, 7. 5 , 75 m g/ k g/ da y fo o d int ak e, increase d li ve r we i g ht , a nd b y s t a nd a rd c on ve r s io n h e p a t oce llul a r enl ar ge me nt a nd vac u o li z ati o n . f ac t o r for o ld e r r a ts R e pro ducti ve T ox ic it y N O AE L

**~** 

### 7 5 m g/ k g/day Reproducti ve Toxicity LOA E L > 

### 75 m g/ k g/ d ay O ff s prin g S ys temi c/D eve lopm e nt a l Tox icity N O AE L 

## = 7
. 5 m g/kg/ d ay Off s prin g S ys temic/ D ev elopm e nt a l T ox icity L O AE L 

## = 75 m g/kg/ da y b as ed o n re du ced pup g ro wth ( re duc e d b o d y we ig h t du rin g la ctati o n ). 

### 870.4100 Se e 

### 4 1 162006 b e low N / A C hro nic t ox ic ity 

### 870.4100 4116 2 001 ( 19 88 ) Sys temi c T ox ic ity NOAE L 

## = 2 m g/ k g/day Chr o ni c Oral A cc e ptabl e/ g uid e lin e S ys tem i c T ox icit y LO A EL 

## = 2 0 m g/k g/da y b ase d o n th e increase d a b so lut e a nd r e la ti ve To x icity ( do g) 

### 0 , 2 , 20 , 200 m g/kg/ d ay in li v er w e i g ht c han ges in m a les s upport e d b y C ap s ul e ge latin cap s ule s h i s t o log ical a nd e n zy m e ch a n ges in th e li ver. admini s tra ti o n 

### 5 2 week s 

### 870.4 2 00 4 1 16 2 005 ( 19 88 ) Sys te mi c Tox ic ity NOA EL 

## = 30 m g/kg/ d ay Car c in o- Ac c e ptabl e/ g uid e lin e S ys te mi c T ox icity LO A EL 

## = 2 25 m g / k g/ d ay b ase d o n li ve r les io n s o b se r ve d in hi g h-d ose ge ni c ity 

### 0, I 

### 0 , 4 0, 200, 1 50 0 p pm m a l e a nd f e m a le mic e. ( m o u s e ) M e an o f b o th s exes 

### evidence of carcinogenicity 7 8 wee k s 

### 0, 1. 5, 6, 3 0 , 225 B ase d o n th e incr e a sed in c ide n ce o f h e patoce ll ul a r n eo p l a s ms ob s er ve d in hi g hm g/ k g/ d ay d ose m a le mi ce, th e c h e mi ca l was rev iewed b y th e H E D Can c er P e e r Revi e w Co mmitt ee (C PR C d oc um e nt dat ed 

### 1 0/ll/ 1 990).

Pa ge 20 of 23

### Table A3.2. 

### Tox ici ty St udie s Profile. G uideline No. MRID No
. (year)/ Results C l ass ifi cation /Doses 870.4300 41 16 2006 ( 1989) Sys temic Toxici ty NOAE L 

## = 7.78 mg/k g / day Co mbin ed Acceptab le / g uid e ! in e Sys t e mic Tox ic ity LOAEL 

## = 39 .41 mg/kg/ da y based o n reduce d body we igh t ga in and/or an Chron ic 0, I 0, 40 , 200, l 000 ppm in c r eased incidence of ce ntril obu l a r T oxic ity/ M : 0 , 0.3 6, 1.48 , 7 ,78, he patoc e ll ular e nlargeme nt and vac uoli za tion Carcin o - 39.4 1 mg/kg/ da y in male and femal e rats , and dec reas ed ge ni ci ty F: 0, 0.43 , 1.81 , 9.37, 47.85 cho lestero l leve l s in fe male rats. (rat) mg/kg/ da y 

### no ev id e nc e of carcinogenicity 1 04 weeks 870
. 5 100 404626 1 2 ( 1 987) No ev idence of mut agen ici ty at conc entr at io n s Bacterial Acce ptabl e up t o th e limit of so lubilit y w ith o r without Rev e rse me t abolic ac ti v itation in S. typh im ur iu m Mutation Test I to 500

**~t plate**  

### without TAI535 , T A I 53 7 , T A I 538, TA98 , and T A t OO S9 activation ; 5 to 1 000 and in E. co li WP 2, u v rA ug/plate vv ith S9 activatio n 870.5375 404626 1 3 ( 1987) The nonacti va ted tes t material was not In v itr o Acce pt ab l e c lastoge ni c; howeve r, in th e presence of S9 mammalian ac ti vation , S

- 3307 0 induced a cle a r do se c hr omoso me 2 X 

### 1 o· S 

### to 2 X 

### l O "" M de pendent cl as tog e ni c res pons e. 

### S 9-activ a ted a berr a ti o n t es t w ithout S9 ac ti va ti o n ; 5 x 

### S

- 33 0 7 D is a c la s to gc n in thi s test sys t e m. (C HO ) I 0" 5 

### to 3 X 

### I O"" M wi th S9 activation 870. 5385 40462615 ( 1987) Neg ati ve for in vivo 

### mi c ro nu c lei inducti on Mam mal ia n Acce pt ab l e w he n co mbined bo ne mar r ow chromosoma l wi th 421 23203 (below) abe rr at io n tes t 870.5385 42123203 ( 1989) Nega ti ve for in vivo 

### mi c ronucle i indu ctio n Mammalian Acceptable w hen comb in ed bone marrow c hr omosoma l wi th 4 04626 15 (above) abe rrati o n t es t 870.5550 40936004 ( 1988 ) Co nduct and r e portin g d e fici e ncies U nschedu led U na ccep t ab le DN A Sy nth es is in Mammal ian Ce ll s in C ulture

Page 21 of 23

### Table A3.2. Toxicity Studies Profile. Guideline No. MRID No. (year)/ Results C l assification /Doses 870.5900 404626 1 4 ( 19 87) Negative for inducing s i ster -chr o matid In vitro sister Unacceptable exchanges (SCEs) in Chinese hamster ovary c hromatid ce ll s treated up to the cytotoxic concentration exc han ge assay range. Top doses demonstrated weak (CHO) gcnotox ic activity in the presence of activation. 870.7485 40496701 ( 1987) Uniconazole was rapidl y abso rb ed , exte nsiv e l y Metabolism Acceptable metabolized, and rapidly exc reted. Over a 3- and pharmacoda y per iod , most (96 -99 p ercent) of th e te s t kinetics compound administered was excrete d from the (rat) animals. The radi oac ti vity recovered in the ur ine, feces , and C02 in the ex h aled air was 40-66, 33-59 and 0. 1 percent of the adm ini stered dose , resp ec tivel y. Peak ti ss ue (includ in g plasma) concentration of radioactivity occurred 1 to 8 h ours after the administration of the te st compound. Three major metabolites were identified in the urine and feces. These repre sen t 83-91 percent of th e administered dose. The metabolites of uniconazole were two oxidation products (58- 75 percent of th e dose) of the m ethyl moiety of the tert-butyl group and a free triazole (3 -15 percent of the do se) lib e ra te d f rom uniconazole. 870.7600 40462616 ( 1 987) The 10 h our absorption va lue i s 7.2% Dermal Acceptable penetration 0.05, 0.5 , 5.0 mg/ rat (rat)

Pa ge 

### 22 of 23

### Attac hm e n t 4
. 

### Uniconazo l e I nternational Resid ue Lim i t Status
. T a b l e A.2. S umm a r y o f US T o l e r a n ces a nd In t e r n at i o n a l MRLs. Un ico n azo l e (U n i co n azo l e-P); P C Co d e 128976; 4 0CF R § I 80
. 643(a) Res idu e D e finiti o ns 

## us Ca n a d a Mex i co• Codex 2 Uniconazolc- P [(E) -(RS)- (4

- (13E)-13 -((4-chlorophenyl)methylene ]-a- ( I , 1- None chlorophenyl)-4 , 4-dimethyl-2-( I H- dim e th y l eth y l

)

- 1 H-1 , 2 , 4-triazol e-1-ethanol , I ,2 , 4-triazol-1- y l )pe nt-1-en-3-ol] , it s including the Z-i so mer [(13 Z)-13-[ (4- R- e nantiom e r and Z-i so m er. chlorophen y l ) m eth y lene]-a-(1 , 1

- dimeth y l ethy l ) -1 H-1 ,2,4-rriazole-1

- ethano l] Co mm od i t y To l e r a n ce (pp m ) ! MRL ( m g/k2) 

## u

s Ca n ada 4 0CF R § I 80.643(a) Ge n e ral Vegetable , fruitin g, group 8 0.01 Tomato crop subgroup 8-09A (0. 0 I )

Completed: 1 2 August 20 15 I. Me x tco adopts US tolerance s and/or Co dex MRL s f or tt s export purpo ses . 2. Th ere are no Codex MRLs es tab li s h ed for uniconazole. Mexico• Co d ex 2



### A tt ac h m e n t 5. 

### S ummary of End-Use Products Co n taining Uniconazole-P. R eg ist r at i o n Acce pt ed %A I F o rmu l at ion Pr o du ct Hom e- App li ca tion M eth od Ty p e N

umb e r D ate Na m e ow n er Use 59639-37 5 D ece mb er 0.055 SL Sumagic Pl ant No Foli a r spray , drench , bulb or 2011 Growth cutting dip , pre-plant R

eg ulator application to soi l s urf ace 59639

- 3 8 5 Dec e mber 78. 1 Technical Valent No For furth e r preparation and 2011 Uniconazole-P manufacture of plant growth Technical regulator formulations 62097-15 7 October 79.7 Technical U ni co n azole- P No For further prep a ration a nd 20 10 Technical manufacture of plant growt h r egulator formulations 62097- 1 8 3 August 2006 0.0 55 SL Co nci se No Foliar spray , drenc h , bulb or cutting dip , pre-plant application to soil surface AL080004 Not availabl e 0.055 SL Sumag i c Pl a nt No Foliar sp ray , drench , bulb or Growth cuning dip , pr e-p lant R

eg ulator application to so il s urf ace



### Page 23 of 23