### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D
. C
. 20460

MEMORAND UM DATE: September 17 , 2015 O FF IC E OF CHEMICAL SAFE TY AND P OL LUTION PREVENTION



### SUBJECT: T riticon azole. Human H ea lth Assess ment Scop ing Doc ument in Support of Registration Review. PC Co de: 1 25620 DJ> Barcode: 0425626 Deci s ion No.: 499940 R eg i s tration No. : NA Petition No.: 1\A R eg ul atory Ac tion: Registration Review Ri s k A ss es s ment Type: S ingl e C h emica l/Aggreg a t e C ase No.: 7036

- 2 TXR No.: NA CAS No.: 131983

- 72-7 MRID No.: NA

**~0** 

### CF R : § 1 80.583 FROM : Nancy Keller, Chemist 

# 6

**~ ;~**  Vincent C hen , Toxicologis t



## ~ Nancy Dodd,

**Chem st~**  **~** 

### Risk Assessment B ranch 3 (i(AB3) Health Effects Div i sion (7509 P) THRO U GH: C hri s tine O linger, Branch C hi ef 

# /JiJ / c.//
..... Risk Assessment Branc h 3 ( RAB3 (){



## ~ Health Effec ts Division (7509 P ) TO : Miguel Zavala. C hem ical Review Manager Risk Management and Implemen ta ti on Branch 3 Pest ic ide Reeva lu a tion Di v i s i on (7508 P) As part of Registrati on Review, th e Pesticide Reevaluation Division (PRD) has requested that the Health Effects Divi s i on ( H E D ) provide a human h ea lth ri sk assessment scop in g d oc um e nt f o r th e fungicide tri ticonazole to support Reg i s trat ion R eview
. To evaluate the scope of work necessar y to support Registration Review , H ED has considered recent risk assessments fo r tri ticonazo l e , u pdates to it s toxic i ty. ex p osu r e, and u sage databa ses, and th e lat est Age nc y sc ie nc e poli cy and risk assess me nt methodolog ies. The mos t rece nt risk assessme nt fo r triticonazole was conduc t ed in 2013 for a new use on gree nh ouse /outdoor ornamen tal s , and a fully updated residential risk assess me nt of a ll existing res id ent i a l uses, including lawns /tur f, gardens , a nd trees, was in cluded (0402683, N. Tsaur , 05 / 30 /2013).

Page I of26Ex ecutiv e S umm a r y Tritico n azo le is a fungicide in t h e tria zo l e c he mical fa mi ly that acts b y inh ibiting the synthesis of ergosterol (s pecifically C -1 4 demethylation). o therwi se known as a s tero l demethylation inhibition (OMI). Trit ico nazo l e is curre ntly registered and formulated f or use as a seed tr eatm e nt for the cereal grain crop groups ( 1 5 and 1 6)
. and for u se o n golf courses. sod fa m1s. outdoo r and greenhouse o rnam e nt al s. r es idential ntrf , re s iden tial ornamentals. and indoo r houseplant s. The t o xi cology da tabase for triticonazo le is comp l e te and adequate for risk assessme nt of the c u rr e ntly reg i s tere d u ses . Based on a weight o f evidence approach considering all the a vai labl e hazard and exposure information. l iED g ranted a wai ve r f o r th e s ubchro ni c inhalati on toxicity s tud y (T X R0056649. K. Rury. 05 /06 /20 13). At the time of R eg i st rati on R ev iew o r the next ri s k assess m e nt. the Age nc y m ay updat e P ODs and to xicolo g ical endpoints sin c e they are con s idered co n servati ve based on upd a ted policie s for endpo in t se lection. A ddition a ll y, the uncertai nty fac tors will be reassessed in the context of the upda ted PODs and endpoint s. T he li ver was th e main ta r ge t o r gan o f toxicity. I n the rat. mou se. and do g repeat do s e oral t ox i c it y s tudi es . the a d ve rse effec t s were manif es ted by fatty vacuo lati o n in the li ve r and adre nal gla nd s: li ve r effect s were al so observe d in o th e r triazole pesticides. Tri ticonazole i s cl ass ified as

..n o t li kel y to b e carcinogenic to h umans·· ba se d o n th e lack of evidence of carc in o ge n ic ity in both th e ra t and th e mouse s tudie s. The 1 OX rood Quality Prot ectio n Act ( FQPA ) Safety Factor was redu ced to I X because there are no re s idual unce rt ai ntie s for pre- a nd pos t-n a tal toxicit y and th e re are no residual unc e rtaint ies in the expo s ur e da tabase. T he residue chemi s try database is s uffi c ient to s upp o rt the current regi strati o ns of tritic o n azo le. The nature o f the re s id ue in cerea l g rai n s and l ives t ock has been adequately defined
. Adequate field trial / processing data. r o tation a l crop data. s torage s tabilit y data , a nd e nfo rcement m e thods are ava il able
.

ew dietar y e xp osure and agg regat e risk assessme n ts are no t a nti c ipated during R eg i s tration Review. unless there a r e s ignificant increases to th e drinking water e xpo su re est im a tes th at n eed to be incorporated. A n upd a ted triazo le ri s k assessment i s also n o t anticipated.

**~ew** res id e nti a l handler and post-application expos ure and ri sk assess m e nt s are n o t anti cipated t o be ne e ded dur ing Regi s trat io n Re view s in ce they ha ve a lread y been updated pr ev io us ly w ith updated SO Ps. Howeve r. occ upational hand ler and po s t - application exp os u r e and ri sk assessme nt s are n eeded during Reg i s tration Rev iew to account for rec e nt changes in exposure assess m e nt assumptions. includin g body weight. amount treated. and tran sfe r coefficients. T he Age n cy will exa min e the need for sp ra y drift and vo latili zation assessments dur ing Reg istrati o n Revi ew f o r triticon azo le based o n the p ot e n ti a l for exposure to b ys ta nders fro m ag r icu lt ura l applications. Howeve r , it i s lik e ly that th e e xisti ng re s ide n tial turf u sc wi ll protect fo r any po tent ial sp r ay drift ap plicati ons.

Pa ge 2 o f2 6Introduction Triti conazo l e i s a fu ngicide in th e triazol c chemical family that blocks growth by disrupting cell membrane formation through inhib ition of ergosterol biosynthesis in fungi. It is curre ntl y registered and fonnu lated for u se as a seed treatment for the cereal grain crop groups ( 15 and I 6). and for u se o n golf courses. sod tarms , ou tdoor and greenhouse ornamentals. residential turf , residential ornamentals. and indoor houseplants. The most recent human health risk assessment for triticona zo le was finalized in 

### 2013 for new uses on o utd oor and greenhouse ornamentals 

### (0402683, N. Tsaur, 

### 05 / 30 / 2013). Triticonazole i s c urren tl y registered and formulated for usc as a seed treatment tor the cereal grain crop groups 

### ( 15 and 

### 16 ), and for use on golf courses , sod farms, outdoor and greenhouse ornamen tals, residential turf, residential ornamentaJs. and indoor hou sep lant s. Homeowners may apply tritic o nazole to residential turf and ornamen tal plant s. Trit ic onazo le e nd u se products are forn1U la te d as so luble concentrates (SC) , wate r dispersible granul es (WG), granules (G) , and liquid s for seed treatment ( L). Appl ic ations can be made with g r ound. aerial. chemigation , and handheld spray equipment. as well as commercia l seed tr eatm en t e quipm ent. Refer to At1achment I for the chemical identity oftriti conazolc. Hazard Idcntificationffoxicolo gy Triti conazole, a triazole fungicide , blocks growth by dis ruptin g ce ll m emb rane formation through inhibition o f ergosterol biosynthesis in fungi. There are no mammalian molecular data t o specificall y demonstrate this mode of action in te st anima l s. The tox icolog y daLabase for triticonazolc is complete and adequate fo r ri s k assess ment of the cwTen tl y registered use s. The s tudies avai lable for risk asses s men t include an acute t ox icit y · battery: s ubchronic oral toxicity s tudi es in rats: a s u bc hroni c derma l toxici t y study in rats ; chron i c toxicity s tudie s in mice. rats. and dogs ; carcinogenici ty s tudi es in rats and mice; prenatal developmental toxicity s tudi e s in rats and rabbits: a r e production and fertility effects study in rat s; a baner y of mutagenicit y stud ie s; metabolism a nd pharmacokinctic s tudi es in rats ; acu te a n d s ubchr on ic n e urotoxicity s tudies in rats: a derma l penetration s tudy in rat s: and an immunotoxicit y study in rats. A detailed description of a ll of the available s tudi es can be found in Attachment 6. The ava ilabl e a bsorption , d i s tribution, metab o li sm, and elimination (ADME) study in rats · indicated that orally-administered radiolabe led triticonazole is rapidly absorbed, widely distribu t ed, partiall y metabolized. a nd clears th e body quickly. The r e was no evide nce of b ioaccum ul ation. In th e rat , mouse, and do g r epeat dose ora l toxi ci r y stud ies. th e adverse effects we re manifested by fatt y vac uo lation in the li ve r and adrenal glands: liver effects we r e also observed in o ther tri azolc pesticides. Increased m otor activ ity was observed at the l imit dose in an ac ut e neurotoxicity s tudy. but there were no indications of neurotoxicity in the s ubchronic study
. There was no indication of increa sed immunotoxic potential in th e T-cell dependent antibody respon se (TOAR) assay .
Page 3 of26The database contai n s prenatal de ve l op mental toxicity studies in rats a nd rabbits a nd a re pro du ctio n a nd fertil ity study in rats. In th e ra t p r enat a l developmental toxici t y study. there was n o evide nc e for in creased s u sce ptibility: developmen tal efTects (e
. g . su p ernum e rary rib s) occu rred at th e same dose as the d ose that caused maternal toxici t y (i.e. dec r ease d body weig ht ). In th e rabbit prenatal developmental toxicit y study. th e r e were n o ind ications o f in c rease d suscep tibili ty 

### in utero. In the rat reproduction an d fert ilit y study. there was no ev id ence of increased s u scept ibility: offspring toxicity (i
.e. decreased pup surv ival and decreased pup body weig ht s) occurred a t th e same dose as parental toxici t y ( i.e. m o rt a lit y. mi c roscop ic l esio n s in adrenals. and dec reased body we ig ht )
. and reproduc ti ve toxicity (i
. e. decreased ferti lity). Overall. there i s no r es idu a l unc e rtaint y for pre / post-natal toxicit y; there i s n o concern for i ncreased s u scept ibilit y in the p r enata l developmental toxicity studies in rats and rabbits and reproduct io n and ferti lity st ud y in rats. The d eve lo pm ental n e uro t oxic it y (DNT) s tud y was waived. The I OX Food Quality Pr o tec ti o n Act (FQ PA) Safe t y Facto r was r educed to 1 X because th ere are n o res idu a l uncertainties for pre- an d post-n ata l tox icit y and the r e are n o residual uncertainties in the exposure database. T riti eonazole ha s been classified as " not li kely t o be carcinogen i c in human s'· based o n the resu lt s of a ca rc in ogen i city study in mice and th e co m bine d chronic toxici ty an d carci n ogenicity s tud y in ra t s (TXR0054249. 

### J. Ki dwe ll. 06 / 1 5/ 2006); the mutag en ici t y s tu dies do not indicate increased mut agenic potentia l in the bat 1ery of 

### in dtro a nd 

### in vivo assays. Th e subchronic inhalation tox ici ty st udy has bee n waived becau se the inhalation m a rgin of exposure (MOE) is greater than the Agency"s level of concern for inhalation waivers(> 1 000) (T X R0 056649. K . Rur y . 05/ 06 / 20 1 3). Triticonazole has lo w tox i c ity v i a th e oral (Tox icity Ca tegory IIJ). dermal (Tox ic it y Category Ill ). and inh ala ti on (Tox ic ity Ca t egory I V) routes: i s n o t an eye irritant (Toxicity Category IV ) or a dermal irritant (Toxic ity Category IV): and is not a dermal sens iti zer. Please refer to Attachment 4 fo r a summary o f the toxicity endpoints and points of departure (P OD s) and A tt ac hm e nt 6 for the co mplet e toxicity pr ofi le t ab le. Co n c lusions: T h e t oxico lo gy database for triti co nazo l e i s adequate fo r ri sk assessment of th e curren t uses. At the time of Registration R eview or th e next ri sk assessme nt. th e Age n cy may update P O D s and toxicological endpoin t s since they arc considered conservative based on updated policies f o r endpo int se le c tion
. Additiona ll y. th e uncertaint y factors will be r eassesse d in the context of the updated PODs and e nd poin t s .

Page 4 of26

### Dietary Expos ure T h e natur e of th e res idu e in plants and li ves toc k com m od iti es has been adequate l y d e fined. Adequ a t e m e t ab oli s m s tudi es o n barl ey, w h eat, dair y cattle, and lay ing hen s are ava il ab le to s upp o rt th e re g i s tered u ses on cerea l g rai n s. T he residue of concern f o r c ereal g ra ins and li ves to c k for th e dietary r isk assessment a nd the toleranc e expressio n i s th e parent comp o und. The most recent d ie t ary risk assess me nt th a t addresses th e t riazo le de ri va ti v e s [I ,2, 4-triaz ole , tri azolylalanine. and triazo ly lac e tic ac id ] includes co nsideration of th e co n t ributi o n of triazo le deri va ti ves fro m the use of triti conazole o n barley and wheat ( 04 26492
. T. Morton, 04 /09/20 15). Adequate enforcem e nt methods are available. An ade qu at e liquid chr o mato g raphy / ma ss s p ect r ometry (LC/ M S) and LC /tandem mas s s pectrometr y (LC / MS / MS ) m e th od ( Meth o d 148.02) is available for the en f o r

cement of the proposed tolerances for triti co nazo le in cerea l g ra in matrice s . Th e val id a t e d limit of q uantitation ( LOQ) i s 0.0 1 ppm tor triticon azo l e inio n a ll cereal grai n crop matrices. A l ivestoc k enforce ment m ethod is not needed si nce no live s tock tolerances are es tabli shed. The data require ments fo r t es tin g w ith multir es idu e meth ods have been fulfilled
. Based on th e results of the te s ting. the multire s idue methods are not appropriate for dete rminin g tritieonazole residues. Adeq uate field trial , proc ess ing , and sto r age s tabilit y data a re available to s upp o rt the established to lera n ces. Adequat e rotational cro p data are avai l ab le. A con t ined rotationa l crop study ind icat e d that it i s unlikely tha t qua ntifi a ble r es idu es of t ritico n azo le (> 0.0 1 ppm ) will be found in rotated c rop commodi ti es at plant-back inter va l s of30 days or greater w hen tritic o n azole is u sed as a see d treat m e nt a t the re g i ste re d l a bel ra t es . B ase d o n th e co nfin e d rotation a l crop s tud y, a field acc umul a ti o n in ro tational c r ops s tud y is n o t r eq uir ed and rotational c r op to lerances are not needed. Th e registered uses fall under 4 0 C FR 

### § 18 0.6(a)(3) for li vestoc k commodities , i .e. altho ug h it i s not pos s ib le to es tab li s h w ith certainty whether tinite r esidues wi ll b e incurr e d. th e re i s no reasonable expectation of fin ite r es id ues in l ivestoc k commodities. This conc lu s ion is based o n dairy cattle and laying h e n metab o li sm s tudie s and l ow ca l cu lat ed di etar y burden s. A cute and chronic die tary ( food an d d ri nking water) expos ur e ri s k assessme nt s w e re conducted in 2013. The acu te and chronic analyses were both unrefined , u si ng tole ra n ce -l eve l re s idu es. I 00% crop trea ted (CT), and con se rvati ve es tim ated drinking wa t er co ncentrati o n s (E DWCs) tor ground water so urces provided by th e E n v ir on me nt al Fate and Effects Di v i s i o n (E FED ). For th e ac ute dietary a nal ys i s, the incorporated EDWC va lue of 520 pp b

**giL)** i s the primary ri s k drive r. The EDW C value was generat ed by the Pe s ticide Root Zo ne Model for Ground Water ( P RZ M- GW). T h e ac ute di e tar y ri sk assessment s hows th a t f or a ll included co mm odities,
Page 5 o f 26the acute dietary ri s k estimates at th e 95 111 percen tile arc no t of co ncern to l-I E D (i.e. < 1 00% of th e acute population- adj u s t ed dose (aPAD))
. For th e chro nic dietary a n a lys i s, the incorporated EDWC va lu e of 16 3 ppb (from PRZM- G W) i s the primary ri sk driver. The non - cance r chronic di etary ri s k assessment s hows that f o r a ll included co mm od itie s. the c hronic dietary ri s k es timat es are n o t of concern to HED [i.e. < I 00 % o f the chronic population-adju s ted d ose (c PAD)l
. Triticon azo le i s classified as ··not lik e ly to be car ci nog e nic to human s: ·· therefore. cance r ri sk was not assessed. Conclusions: A new dietary exposure as sess ment i s n ot a n t icipate d t o be n ee ded during Reg i s tra tion Revie w unle ss there a r e s ig ni ficant increases to th e dri n king water exposure es timate s. 

### R es id e n tia l Ex po s ur e T ritic onazo le is currently regis ter ed for use in re s idential se ttin gs o n turf and ornamental plants. T h e re i s potential for s hort-term re s ide n tial exposure t o triticon azo le during handling (mix ing , loadin g. and a ppl y in g) and pos t- applicat ion activities. R

es id e nti a l H a ndl ers Va ri ous tritic o nazo l c lab e l s of varying formulations indicate that triticonazole i s reg i s tered for u sc on re s id ent i al turf and o rnam e ntal s. P reviou s residentia l exposure and risk assessme n t s for triticon azole were conducted at the maximum r egis ter ed application rate and incorp o rated the re v i se d 20 1 2 Res identi al SOPs ( D4 09 74 3. N. Tsaur. 03 /07 / 2013). Applicati o n s can be m a de to turf and o rnamental s via hand held spray equ ipment for liquid s and via hand for granu les. R

esi dential handler ( inhal a ti o n o nl y) mar gi n s of exposure (MOEs) ranged from II 0.000 t o 6.600.000.000. and are not of concern. D e rm al ri s k esti mates were no t conduc t ed because a dermal ha zard was no t ident ified for triti co nazo l e. Re s id e ntial Post-Appl icati o n S hort-term incidental o ral exposure and ri s k estimates were previous ly rea ssess ed u s in g th e 2012 Res id e nt i a l SOPs ( 040974 3
. N . Tsaur. 03 / 07/ 20 1 3). D ermal ri s k estimates for adult s and c hildren we re no t conducted because a derma l ha7_ard was no t identified for tritic o n azo le. Pos tapplication MOEs we re not of concern for any of the register e d residential u ses oftriticon azo le . Th e s h o rt-term incid e nt a l o ral MOEs for c hildren I t o < 2 years o ld ran ge from 1.400 to 1. 300
. 000. S pray Dri ft or Volatilization Res id e ntia l bystander exposures r es ul ti n g fro m off
- s ite tran s p o rt (e.g. s pray drift or volatili zati o n ) may occ ur as a r esu lt of applications of triticonazole. The potential for s pray drift will be e va lua t ed for each p es ticid e durin g the Registrat ion R eview pr ocess wh ic h ensures that all us es f o r th at pe s ti cide wi l l be considered con c urrentl y. Th e a ppro ach i s o ut l ined in th e rev ised (2012) S tandard Op eratin g Proc ed ur es fo r Re s id e ntial Risk Assess m e n t (SO P s)
- Res id e nti a l Expos ure Assess ment S tand ar d Ope r ating Proce dures Adde nd a I : Co n s idera tion of

Pag e 6 of26Spray Drift. Th i s document outlines th e quant i fication of ind irect non-occupational exposure to drift. In term s of volatilization. the agency has developed a Volatilization Screeni ng Tool and a subsequent Volatilization Sc re e n ing Analysis (h ttp: //\v"\-\W.rC!.!ulations.gov /# !docketDetail:D = EP 1\-IIQ-OP P- 20 14-0219). During Registration Review. the agency wi ll util ize thi s analysis to determine if data ( i. e. flux s t ud ies. r oute-specific inhalation tox ico l ogical s tudie s) or further ana lys i s is required for tritic onazo le. 

### Conclusions: There a r e registered residen ti al uses of tritic onazo le th at h ave been assessed u si n g the maximum application rates and revi se d 20 1 2 Re side ntial SOPs. Therefore. a residential hand le r and pos t -applic a t ion assessment i s not requ ired duri ng Re gist ration Re v iew
. The Agency will examine the need for a volatilization assessment , as well as evaluate th e potential triticonazole exposure from spray drift during Registration Review. Ho weve r , it is likely tha t the exis tin g residential t urf u sc will protect for any p otent i al spray drift applications. 

### Aggregate Ri s k Assessme nt Aggregate assessments co n s id er exposures from food , drinking wa ter, and res ident i al u ses. Since there are residential uses of triticonazo le. aggregate risk considers re side nt ial handler and post-application exposures. food. and drinki ng wa ter. In the mos t recent human health risk assessment (0402683, N. Tsau r , 05 / 30 / 2013), an acute aggregate risk assessme nt , which is e qui vale nt to th e ac ute dietary ri sk assessment, was not of conce rn to H ED. On ly females 13-49 years old were assessed, since an acute endpo int of concern was not identified for the general population. A shon-tem1 aggregate ri sk assessment was conducted for ad ult s and children
. for adults , the pathways leading to aggrega te expos ure include oral d ietary (bac k g r o und ) an d inhalation ( primary) routes. For children , the pathways leading to aggregate exposure include oral dietary ( background) and in c id en tal o ra l (p rimary) r o ute s. The adult a nd children s h ort-term aggregate dietary and re s idential MOEs are I00.000 and 1 .400. respectively ( LOC = I 00). Chronic exposu r e from th e residential pathway is n ot anticipated based on the current triticonazole use pattern. Therefore. th e chronic aggregate risk (food and drinkin g water) is equivalent to the chr o nic die tary (food and dri nki ng wate r ) exposu r e estimate, whic h was not of concern to HED. Co n clusions: Aggregate exposure to triticonazole i s cu rrentl y not of concern to HED. New aggregate assessments arc not ant icipated to be needed during Reg i s tratio n Rev iew, u nless c han ges in u ses. procedures. or estimated drinking water concentrations occur.

Page 7 of26

### O cc up a ti o n a l E xpo s ur e T ritico nazo l e i s registered for use as a seed treatment on cereal gra ins (crop g r oups 15 and 1 6): industrial/commercial turf grass ( including golf course tu r f, sod farms. seed farms. college and professional s po rt s fields. and residential and com mercial lawns): and on orna m enta l s in greenhouses and fields. There is potential for short
- and intermediate-term occupational expos ure t o triticon azol e during handling (mixin g. loading, and applying) and post-application ac ti v itie s. Occupational Handlers The regi s tered triticon azole labe ls requi r e occ upational hand l ers to wear lon g s leev ed shirts. lo ng pan t s , s hoes. soc ks. and chemical re s istant g loves. Applications can be made usin g ground. aerial. chemigation. and handh e ld spray equipment. a s well as commercial seed tr eatment equipment. Although so m e of the updated occupational ex po s ure assessment policies and body weight assumptions were in co rporated into previous triticonazolc exposure assessments. updated occ upational handler a nd p os t-application assessme nt s wi ll be needed f or some occupati onal sce nario s. A ll current occupational handler MOEs are n ot of concern (MOE > I 00). Occupat ional Post
- Application A dermal endpoint was not iden tified for triticona zo le: therefore. a n assessment of occu pational defiT!al post-application expo s ure t o tritic onazo le was n ot conducted. Based on th e Agency's c urrent practice s . a quantitative post-appl ication inhalation exposure a ssess me n t was not performed for triticonazole at thi s time. If nevl po l ic ies or proced ure s are put int o p lace. the Agency may revi s it the ne ed for a quantitative occupational pos t-app lication in halation exposure assessme nt f or triticonazolc. 

### Concl us ions: The r e is s ufficient inf o rmation availab l e to assess occupational hand l e r and postapplication exposures. Updated occupational handler and post-application exposure assessments will be conducted during Registration R ev iew for the fu ll reg i s te r ed u se profile of triticonazole.

Page 8 of26Public Health a nd Pestic id e Epidemio logy Data Based o n the low frequenc y and severity of incident case s reponed for triticonazo lc in both the OPP Inc ident Data System ( I DS) and the Ce nt e rs for Disease Control and Pr eve ntion / Nat iona l Institute for Occupationa l Safety and Health (CDC/N IOSH) Sentinel Even t Not i fication Sys tem for Occupati onal R i s k-P es ticide s (SENSOR), th e re does not appear to be a concern at this time that would warrant further in ves tigation. For the Main IDS, from January I, 20 I 0 to February 4. 2015
. there were no incident s r eponed involving triticonazole. In Agg r egate IDS , from January I. 2010 to February 

### 4, 20 15 , there were thr ee incidents reponed invol v in g triti co nazol e. These incidents wer e classified a s min o r severity. Overall. th e r e are few incid e nts rep o ned to IDS involving triticonazole. A query of th e Se ntin el Event Notification System for Occupationa l Risk (SENSOR) -P est i cides database for 1998-2010 identifi ed no cases invo lv ing triticonazole. The Agricul tu r al Health Study (AI-IS) is a high quality, prospective epidemiology study evaluating the link between pes ticide u se and various health outcomes including cancer. T he A I-I S includes priva te and co mm e r c i

a l pesticide applicators and their spouses. If there are AHS findings rele va nt to a particular pesticide going through registration review , the Age n cy will ensure the y are co n sidered in the p r obl e m formulation!scoping phase of the pr ocess and. i f appropriate, full y re v iewed in the risk asse ss me nt phase of the process. The A I
- IS in c lud es information on u se o f 50 di ITerent pesticide active ingredi e nt s co mmonl y used in agric u lture. Triti conazole is not in cluded in the A i lS. and ther efore
. thi s study do es not provide information for this report . 

### The Agency will continue to monitor th e incident in f ormatio n and if 

### a concern is triggered. add ition al analysis will 

### be includ ed in the ri s k assessment. Co nclusions : Bas ed on the low frequency and low severity of incident cases reported for triti co n azo l e in b o th IDS and SENSOR-Pe s ticides databases. there do es not appear to be a conce rn at thi s tim e that would warrant further in vestigation. The Agenc y will continue to monitor the incident information and if a concern is triggered , additional analysis will be included in the ri sk ass ess ment.

Page 

### 9 of26Tolerance Assess ment and Int ern ation a l H a rmonization Tole r ances are established for plant commodities under 40 CfR 

### § 180.583(a) for residues of th e fung icid e triticonazole, (I RS)-(E)-5-[(4-chlorophenyl)methylene]-2.2-dimethyl -1- ( 1 

### H-1.2.4- triazol-1-ylmethyl)cyclopentanol. on cereal grains (grai n s. forage. f od d er. and straw) fr om th e treatmen t of seed prior to p lan ting. The crop group tolerances are es tablished for ..grain. cereal. forage. fodder, and straw. group 16. except rice .. at 0.10 ppm and for grain. cereal. group 15. except rice .. at 0.0 1 ppm. No tolerances are estab li shed on l ivestock commodities
. No tolerances are established for Section 18s. regional registrations. or indirect/inadvertent residues. The tolerance expression in 40 CfR § 180.583 should be modified to add a compliance s tatement as f o ll ows: "To l erances are establ i s hed for residues o f th e fungicide triticonazole. including its m etabolites and degradates, from the trea tm ent of seed prior to planting. in or on the commodities in the table below. Comp lian ce with the tolerance levels specified below i s to be dete rm ined by m easu rin g o nl y (5£)-5-[( 4-ch lorophenyl)methy lene]-2.2-dimethyl-1
- ( I H-1.2.4-triazol-1- y lrneth yl)cyclopentanol.·· As shown in Attachment 3. there a r e no Codex ma.ximum res idue limits (MRLs) established fo r triticonazole: therefore. there is no harmon ization issue with Codex at this time. E nvironmental Ju sti ce Potential areas of e n vironmen tal justice co ncerns , to the extent possible. "viii be considered in the registration review. in accordance with US Executive Order 12898. "Federal Actions to Address E n v ir onmen t al Justice in M in o ri ty Popul a tion s and Low-Income Populations." http: // www.eh.doc.gov /oep a/guidance / justic c/ eo 12898.pdt). As a part of every pesticide risk assess m ent. OP P co n s iders a l ar ge variety of co ns umer subg r oups accordi n g to well-estab l ished procedures. In line w ith OPP policy. HED estimates risks to population subgroups from pes ti cide expos ur es th at are based o n patterns of th at subgroup·s food and water consumption. and ac tivities in and around the home that involve pesticide use in a resident ial setting. Ex t ensive data on food consump ti o n patterns a r e compiled under the N HAN ES/WWE I A and are used in pestic ide risk assessments fo r all regi s tered food uses of a pesticide
. These data are analyzed and categorized by subgroups based o n age and ethnic g r oup. Additionally. OPP is able to assess dietary exposure to smaller. specialized subgroups and exposure asse s sments arc performed when conditions or circumstances warrant. Whenever appropriate. non-dietary exposures based on home usc of pesticide products and associated risks for adult appl icat ors and for toddlers. youths. and adults entering or p l ay in g on treated areas post-application are eval uated
. Fu rth e r considerations are currently in development as OP P has committed resources and expertise to the development of specialize d software and models that consider exposure to bystanders and farm workers as well as lifestyle and tradit ional dietary patterns among spec i fic subgroups.

Pa ge 10 of26C u m ul at ive Triticonazole is a member of the triazole-containing class of pesticides. Although conazo les act si mil arly in plants (fungi) by inhibiting ergosterol biosynthesis , there is not necessarily a relationship between th e ir pesticidal activity and th ei r mechanism of toxicity in mammals. Structural si milaritie s do not constitute a co mmon mechanism of toxicity . Ev i d e nce is needed to estab li sh that the chemicals operate by the sa me. or essentially the same, sequence of major biochemical events. In conazoles. however. a variab le pattem of toxicological responses is found. Some are hepatotox ic and hepatocarcinogenic in mice; some induce th yro id tumors in rats: and some induce developmental. reproductive, and neurological effects in rodents. Furthermore. the conazolcs produce a diverse range of biochemical events including altered cholesterol leve ls. stress responses, and altered DNA meth y lati on. It i s not clearly understood whether the se biochemical even ts are directly connected to th ei r toxicologica l outcomes. Thus. there is curre ntl y no evidence to indicate that conazoles share com m on mechanisms of toxicity and EPA is not fol l owing a cumulati ve risk approach based on a common mechanism of toxicity for the conazoles
. For infom1ation regarding EPA · s procedures for cumulating efTec t s from substa n ces found to have a commo n mechanism of tox icit y. sec EPA·s website at http: // www.epa.gov/ pesticidcs / cumulative. Triticonazole a nd other triazole-containing pesticides can f orm the common metabolite I ,2,4- triazole and two triazole conjugates ( tri azo lyla l anine and triazolylacetic acid ). To s upport existing tolerances and to establish new tolerances tor triazo le-derivative pesticides , including triticonazole. U .S. EPA conducted 

### a human health risk assessment for exposure to I ,2 .4-triazole. triazolylalanine , and tria zoly lacetic acid resulting from the use of 

### all current and pending uses of any triazolc-derived fungicide. The risk assessment is a highl y conse rva tiv e, sc reening- leve l evaluation in tem1s ofhazards assoc iated with common metabolites (e.g., use of 

### a maximum
. combination of uncertainty factors ) and potential dietary and non-dietary exposu r es ( i.e
.. high end estimates of both dietary and non-dietar y exposures). In addi ti on, the Agency retained th e additional I 

### OX FQPA safety factor for the protection of in fants and children. Th e assessment include s eval u a ti ons of ri sks for various subgroups, including those comprised of infan ts and children. The Agency's complete risk assessment is found in the propiconazole r eregistration docket at hnp: // wv,rw.regulations.gov, Docket Id ent ification ( ID ) Number EPA-HQ-OPP-2005- 0497. The r egis t ered uses of triticonazole do not result in incre ases in dietary exposure estimates for free triazo lc or conjugated triazoles and thu s, no updated risk assessmen ts are need ed for the triazolc derivatives (0426492. T. Morton , 04 / 09/20 15). H um a n Studi es The risk assessments which have been previously conducted for triticonazole relied in part on data from stud ies in which adult human subjects were intentionally exposed to a pe s ticide to detenninc their dermal and inhalation exposure. Many such s tudi es. involving expos ure to man y different pesticides. comprise ge neric pest i cide exposure databases suc h as th e Pest i c i de Handl ers Exposu r e Database (PHED), the Outdoor Re s id e nti a l Exposure Task Force (ORETF). the Ag ri c ultural Reentry Task Force ( ARTF) Database; and ExpoSAC Policy 14. 15. and 15.1 ( SOPs for Seed Treatment). E PA has re viewed all the studies s upporting these multi-pesticide Pa ge II of26generic exposure database s . and has found no clear and convincing evidence that the conduct of any of them was e ith er fundamen tall y unet hi ca l o r s i g n ificantly deficie nt relati ve to the e thi cal s ta nd a rd s prevailing at the t i me the r esearch was conducted. A ll app li cab l e r equi r e m e nt s of EPA·s Rule for the Protection of Human Subjec t s of Re searc h ( 40 CFR Part 26) have been sati sfied
. and th e re i s no regulatory barrier to continued r eliance on these studies.

**tta** D e ficiencie s No toxicologicaL r esidue chemistry. or occupationa l and r es id en ti al exposure data are needed to s upport the registered u s e s of t rit iconazo lc at this t ime .

Page 1 2 of26Reference s Recent Memoranda Re leva nt to Registra tion Review ofTriticonazo le Author DP!fXR # Date Title Ri sk A ss e ssme nt W. Wasse ll D27327S 09/04 /2002 P P

#9F06051; HED Ri sk Asses s ment: Human Health Ri s k Assessmen t for First Food Usc ofTri tic onazo le for Seed Treatment Uses on Wheat and Barley. M. Doherty D322215 02 /07/2006 1.2.4-Triazole, Triazole Alan ine. Triazole Acetic Acid: Hum an Health Aggregate Ri sk Asse ss ment in S upport of R e r

eg i srration and Regis trati on Actions for Triazole-derivative Fungicide 1 Co mp _ounds. S. Winfield 031661 2 / 12 /20/2006 Trit icona zo le: liED Human H ea lth Risk Assessment for Pro p osed 0313844 Use on Turf. PC Code: 125620. Reg Nos. 264-AN R, 432-REAI. DP Numbers 316612 an d 3138-l.t. N. Tsaur D35861.t 08/07/2009 Triticonazole. Human Health Risk Assessmen t for Proposed See d Treatment Use on Cereal Gntins (C rop Group 1 5) In clud ing Barley , Field Corn. Oats. P opcorn. R ye. Sorghum Grain. Sweet Com. Triticale. and Wheat (Excluding Rice ): and forage. Fodder, and Straw of Cereal Grains (Crop Gro up 16), Excluding Rice. N
. T sa ur D372454 08 /30/2010 Triticonazole. Human Health Ri sk Asse ss ment for Proposed Residential Handler Use on Turf. Omantcntals
. and Indoor Houseplant s . N. Tsaur 0402683 05 1 30 !20 13 Triticonazole. Aggregate Human Health Risk Assessment for Propo se d Use on Ornamentals (Outdoor nnd G r eenhouse) with U

pdated Residential Ri sk Estimates of All Existing Residential Uses ( Lawn s/Turf: Gardens and Trees). Re s idu e C he mi s try N. Dodd 0262566 06/06/2001 PP#9f06051. Tri ti conazolc Seed Treatment on Barley and Wheat. Review of Analytical Me thod s and Re sidue Da t a. First Food Us c Review
. N. Dodd 0281088 05 1 11 /2002 PP #9F06051. Triticonazole Seed Treatme nt on Barley and Wheat.

**harter ~''**  brand PB Fungicide Label. R ev ise d ChartcrT'' brand Triticonazole

**Fun~icide** label. A. Acierto 0325956 06 / 12/2009 Triticonazole. Application for New Seed Treatme nt Uses on Cerea l G

r ai n s (E xcept Ri ce) (PP#8F7420)
. Summary of Analytical

. Chemist!) and Re s idue Data
. S. Funk D370705 10 /30/2009 Triticonazole. Application for New Seed Treannent Uses on Cereal Grains (Excep t Ri ce) ( PP#8F7420). Amendmen t to Labe l and Request for Removal of Plan t Back Interval Restriction s Requ iremcnt. D
. Drew 0363016 06/ 12/20 12 Storage Stability of 1 ,2.4- Triazole. Triazolylalanine and Triazolylacetic Acid in Various Crop Matrice s and Pro cessed Co mmodities (up to four years under frozen s torage)
. Di et arv Expo s ure Asses s m ent N. Tsaur 0409744 04 / 10 /2013 Triti conazole. Acute and Chron i c Aggregate Dietary (Food and Drinking Water) Exposure an d Risk Assessment for th e Sec t ion 3 Registration Ac tion t o Add New Uses on Outdoor and Greenhouse Orname ntals. Occupational a nd Residential Exposure Assess m e nt N
. T s aur 0409743 03 /07/2013 Tri ti conazole. Occupational and Residential Exposure Assessment for a Pr opose d Us c on Oman1ental s with An U pd<I!Cd Residenti a l Exposure Assessment of All Exis ting Re s idential Uses (Lawn sf rurf: Garden s and Tree s ). Page 1 3 of26R e cent Memoranda Re l e va nt to Reg is trati o n Re v i e w o fTriti co na zo le Author 

# I DPffXR # 

# I Date 

# I Titl e I n ci dent Rep o rt S. Recore 

### l 04 2 8796 

### I 04 t 01 12015 

### I T riticonazole: Tier I Revi e w o f Human Incidents 

### Attachment s I. Chemical I dentity Table 2. Ph ysicoche m ical P rope rt ies of T eclmical Grade Triti conazole Table 

### 3. Tolerance/MRL Sum m ary Table 

### 4
. En d poi nt Se lec tion Tab l e s 

### 5. Tox ico logy Data Requ i reme nt s 

### 6. Toxicity Profil e Tables

Page 

### 14 of26Attnc h mc n t I C hemica l Id e n tity Tab le T r iticonazo le Nomenclatu re Chemical stru cture



# ~~

**I** N 0 11 H

3 C H3C :;:;.---- 

# I **~**hCl Common name T riticonazo l e Company experimental name BAS 595 F (fom terl> ' RPA 4000717) IUPAC name (R S) -(£)-5- ( 4
- c hl orobe nzylidene)-2.2-dimethyl-1-( 1// -1.2.4- tria zo l-1- ylmethy l)cyclopentanol CAS n am e (5£)-5 -[ ( 4-chlorophenyl)methylene ]-2.2-dimethyl-1-( I/-/-1 .2.4-triazol-1- ylmethyl)cyclope nt ano l CAS regisrry number 13 1983-72-7 Chemical structure ofT

**N~** metabolite 

### I

**N~** 1.2.-t-triazol.: Che mi ca l s tru ctu r e o fT A 1H

**N~** metabolite

**~** 

### I



# HO~N-__§N 0 triazole alanine or triazolyl a lanim: Chemical structure ofTAA 0

**N~** m e tab o l it

e



## I I

**N~** HO t r i azole acetic acid or triatnlylac.:tic acid

Page 1 5 of26Attachment 2 Phys icochemic a l Pr ope rties of Techni ca l G r ade Tri ticooazo le Ta ble

Phys icoc h e mical Properties o f the Technica l Grade Triticonazo lc Parameter Valu e Reference Me ltin g poim ( 0 C} 1 40 °C: PAl di splays two cr ys talline foml s meltingarl3 7 and 1 4 1 

## o c pll Not available Density at 20 ° C (glmL ) 1.21 g/ mL (PA l ) Water s olubility ( at 20 ° C) 8.4 m g/L at 20 

## oc Solvent Solubi li ty ( gi L) H

ex an e 0
. 12 giL Methanol 18
. 2 giL So lvent s o lu bility (at 2 1
. 2°C) Ace t o n

e 74 .5 giL BA S F document number Toluene 12.6 giL 2002110 I 6091 " Dich loromcthanc 19 1 giL

E

th yl acetate 48
. 6 gi L n-Octanol 6 . 2 gi L Vapor pre ss ure at 25 ° C < 0
. 1 X IQ •S PA at 50 °C Dis sociation con s tant ( pK. ) D o cs no t dis s ociat e Octan o llwater panit ion coefficient Log P = 3
. 29 at 20 °( UV / vi s ible ab s orpt ion s pectrum No t a vailable

**~** a As re f erenced m MR I D 4 7 4 7020 .>.



### Page 16 of26

### Athlchment 3 To lcra n ce / MRL Tabl es nuconazo e _) 

## - , a t e o 

### fR eq ue s t 

## - ) Summary of US and Internationa l To lerances and Maximum Resid ue L imits Residue D efi nirion ' 

# us Canad a Mexico 3 Codex -10 CrR *180.583 ( 5[; )·5 -l (

-1-ch luroph.:ny l)mc th yknc J-2.2 • Triticonazolc. ( IRS)-(E )
- 5 ·( (4-

**ch oro**  **ph.:n~ l)m..:thyl.:n.:J-2.2-dim..:th)**  1 -1- ( IH- dim.:th) I· I· ( 111-1. 2.-l-tri:vol -1- No ne 1.2.4 -trinzol-1-vlm.:tlw l)cy lop.: ntan ol ylmo.:thyl)cyclopcntanol Commodity To le r ance {ppm} /Maximum Resid ue Limil ( mglkg) 

# us Ca n ada Mexico 3 Codex Grain. cereal , forage, fodder and 0.10 s traw. gro up 16. e xcept ric e 0.0 I barley
. field co m. oat s . popcorn Grain
. cereal , group 15 , except rice 0
. 01 grain. rye, s weet com kernel s plu s cob with hu sks removed. Lriticalc. wheat Comple t ed: M. cgussie: 07/2 7/2015 a Mcxtco adopts US t olerances an d/o r Co dex MRLs for tiS cxpon purposes.



### Page 17 of26

### A tt ac hm ent 4 E ndp o int Selec ti on T ab les
S umm a r y o f T ox ico lo g i cal Do ses a nd E n dp o int s f o r u se in D ie t ary and No n - Occ upati o n a l H u m a n H ea lth Ri s k Asse ss me n ts Expos ur e Point of U nce rt ai nty I RfD . PAD. Level FQPA Safety ofConcern for Study and Toxicological Effects Scen a rio D eparture ( POD) Fac tors R isk Assess m e nt Acute Di etary NOAEL = U F " = lOx a R fD = Ac ut e Neurotoxicitv Stud v - Rat Ge n eral 400 m glkg U Fu = lOx 4 mglkgl day LOAEL 

## =2000 mg/kg population FQ P A SF = IX Based on in creased mo tor activity ( incl u d in g infants aPAD = in both sexes. and children) 4 mglkg/day Ac ut e Die t ary Developmental UF,, - lOx aRfD
- Prenatal DeveloRme n tal T oxici t v Females ( 13-49 NOAEL = UFH = lOx 0 .5 rn gfkg/ day
- Rabb it years o l d) 50 rn g!kg/day FQPA SF = IX Development al LOAEL 

### = 75 a PAD = mgfkg / day 0. 5 mglkg/ d ay Base d on cra n ia l va riation s, abortion, and increased pre- and pos t-i mplanta t ion losses ass um ed to occu r follow i ng a s ingle dose. C h ronic Dietary NOAEL = UF,, - lOx cRfD = Carc inogenicitv
- Mouse 17.4 m glkg/day U Fu = lOx 0 . 1 7 mglk g/ day LOAEL 

## =202.2 m g!kg/day FQPA SF = IX Based on decreased body weight cJ>AD = gain and liver toxici t y (e.g. 0. 1 7 mglkglday hepatocy t ic large fatty vacuo lati o n ). I ncidental Oral Maternal U F , = IOx Residential LO C Prenatal Deve l oR m en t al Toxic ir v Short Term NOAEL = 25 

### ur.. = l Ox for MOE = 100
- Rabbit ( 1 -30 day s) m g/kg / day FQPA SF = IX Ma t ernal LOAEL = 50 m glkg/ day Base d on dec r eased body weight gain. r educ ed food consumption. and morta lit y. lnciaenta l Oral NOAEL = U F " "' l Ox Res ide nt ia l LO C Carcinogen icitv
- Mouse In t ermedia t e Term 17.4 m glkg/d ay UFu = lOx f or MOE = 100 LOAEL = 202.2 mglkg lday ( 1-6 months) FQ PA SF IX Ba se d on decreased body weight gai n ::md liver toxi ci ty (e.g. hepatocy t ic large latty vacuola t ion) . Dermal Q u an t ification of dern1al ri sk was not conducted . Dennal absorption is minimal ( < 2% of th e Short Tenn total administered dose) reg ardle ss o f do se. and rat s treated by derma l occlus ion for 6-7 ( 1-30 days) hou rs/ day for 23 day s at dose s up to I 000 mglkg/ day ( Limit-Do se) did n o t exhib it any s ign s Intermedia te Term of syste mic toxicity or dermal irritat ion. and no treatment - related hi s topathology findings 

### ( 1-6 month s) were noted. Long Tcnn (> 6 month s Inha l a ti on Maternal UF" = lOx Reside nti al LO C Prenat al DevciOU!llCn t al Toxicit\' S h ort Term NOAEL

**~** 25 U Fu - lOx for MOE = 100
- Rabbit ( 1 - 30 days) mglkg l day FQPA SF = IX Maternal LOAEL = 50 m gfkglday Oase d on decreased body weight ga in. reduced food consumpti on. and monal ity.



### Page 18 of26i S ummar y of To x ico logica l Do ses and Endpoint s f or u sc in Dietar y a n d No n- Occupa ti onal Hum an He a lth Ri s k Assessments Expos ur e Point of Unce rtainty I RfD. PAD, Leve l FQPA Safety of Conce rn for S tud y and Toxico logical Effec t s Sce nari o Departure ( P O D ) Fac to rs Ri s k Assessmen t Inhalation NOAEL = UF ,, = l Ox Residential LOC Carcinogcnici t v- Mouse Int ermedia t e fenn 17.4 mglkglday UFu = lOx for MOE = 100 L O AEL = 2 02.2 mglkg/ day ( 1-6 month s) FQPA SF = IX Based on decreased body weig ht gain and liver toxicit y (e.g. hepa t ocy ti c l arge fatty vacuolation)
. Ca nce r ( oral , C lass ifi ca ti on: " No t lik e l y t

o be Carcinoge n ic t o Human s · • based on the absen ce of s i gn ific ant dermal. and tumor increases in two adequa t e rode nt carci n ogenicity s tudies ( TXR0054249 , J
. Kidwell , inhalation) 06/ 15/2 006)
. Pomt of Departure (POD) = A data pom t or an es tm wted pomt th atss denved from observed dose -respo n se data and used to mark the beginning of extrapolation to detem1ine risk associat.:d 11 ith lmn:r .:m iromm:ntally r.:lcvant human exposures. NOAE L = no observed adverse dli.'Ctlcvd
. LOAEL lo11c:;t

**ob~ened** ad 1 ·erse cfTectlen:l. UF = uncertainty factor
. UF" = extrapola tion t'rom a nimal to human (intcrspccies). U Fu = potcntial variation in sc nsitivi t y among mcmbers ofth.: hum;m popula ti on ( intrnspccic s)
. fQJ>A S F = FQPA Sa lt:ty Factor
. l'viOE = margin of ex pos ure. LOC = kvel of conccm. N /A = not app li cnble
. Summary of Toxicol og ical Do ses a nd Endp oi nts f or u sc in Occupat io nal Human H ea lth Ri sk As sess m e nt s Ex po s ure Point of Uncertai nt y I I UD, PAD, Level Sce nar io Dcpanure ( P oD) FQPA Safety of Concern for St udy and Toxicological Effects Fac t ors Ri sk Assessment D er ma l Quantification of denn al ri sk wa s not conducted. D e rm a l ab so rpti o n is minima l ( <2% of th e S hort Term t ota l administ ered dose) re ga rdl ess of dose. and rats treat ed by dem1a l occl u s io n for 6-7 ( 1-3 0 days) hours/ day fo r 23 days at doses up t o 1000 mglkglday (L im it-Dose) did not exhibit any signs lnt e m1ediate Term of sys t e mi c toxi ci ty or denna l irritation , and n o tr ea uncnt
-r c lm cd hi s topathology finding s ( 1- 6 mo nth s) were n o t ed. Lon g Term ( > 6 months Inh alation Matcmal UF "

- lOx Occ upati o na l Prena ta l

**cve loQm** 

**nt al**  **To**

**it ~**  S h o rt Tc m1 NOAEL = 25 UFu

- lOx LOC fo r MOE = - Rabbit ( 1-30 days) mglkg!day 100 Maternal L OAEL = 50 mglkglday Based on dec re ased body wei g ht ga in, r edu ce d food co nsumption , and mortalit y. Inh a l ation NOAEL

- UF "- lOx Occupational C arcinogenicitv

- Mouse l nt enncd iate Tc rn1 I 7.4 mg/ kglday UFH
- lOx LOC for MOE = LOAEL

- 202. 2 mglkg!day ( 1- 6 mo nlhs) FQPA SF = 1 00 O as ed on decreased body we ight IX gain and li ve r toxicit y (e.g. hcpatocytic large fatty vacuolation). Ca nce r ( dermal Classi ficati on: "No t lik e l y t o be Ca rc ino ge ni c t o Human s'' based on th e abse n ce of and inhalation ) s ignificant tum or increase s in two adequa t e rode nt carcinogenicity s tudi es ( TXR 0054249. J
. Kidwell. 06/ 15/2006). Posnt of Dcpartun: (PoD) = A data pomt or an estimat ed pomt tha t 1s dcnved from observed dose-response data :usd used t o · mnrk the beginning of extrapolation to det cn ninc risk associutcd with I O

I\ Cr cnv ir o nm cn tall y rele v ant human cxposurcs. NOAEL "" no observed adverse effect lcvcl. I. O t \EL

- lcmcst ohscrl'cd adverse c!Tect lcvcl. F = un certainty f ac tor. UF" 

### = cxtr:tpolmion from :mimalto human (intcrspccic s )
. U Fu = posential va ri a ti on in scnsiti \

**it ~**  among

**mcmb~rs** of the hum;m population (intraspccics). FQPA SF = FQJ>A Sa fct y Factor. 1\ • IOE

- mar gi n o r exposurc. LOC = lcvcl nf concern. N /, \ = not app li cable.



### Page 19 of26

### A ttachm e nt 5 To x icolo gy Data Requirement s The r eq ui re m ents (40 CFR 158
. 500) for food u ses are in the tabl e below. Use of the new guidel i ne numbers does n o t imply t h at t he new (1998) gu i de li ne pr otoco l s we r e used.
T oxico l ogy D a t a Requir e m e n ts Guide l ine Study Type Required S ubmitted 870.1100 Acute Oral Toxicity Yes Yes 870.1200 Acu t e D ennal Toxici ty Ye s Ye s 870.1300 Acute Inhalation Toxicit y Yes Ye s 870.2400 Acute Eye Irrit at io n Ye s Yes 870.2500 Acu te Dennal Irritatio n Ye s Yes 8 70.2600 Skin Sensitization Yes Ye s 870.3100 90-Day Oral Toxicity in Rodents Yes Yes 870.3150 90-Day Oral Toxicity in Non
- Rodent s Ye s No 870.3200 21 / 28-Day Dennal Toxicity Yes Yes 870.3250 90-Day Dem1al Toxicity C R No 870. 3465 90-Day Inhalation Toxici t y C R No Prenatal Developm en tal Toxicity Study ( Rat ) Yes Yes 870 .370 0 Prena tal D eve lopment a l Toxicity S tudy (Rabbit) Yes Yes 870.3800 Reproduction and Ferti lit y Effects Ye s Yes 870.4100 Ch ronic Toxicity ( Rodent) Yes Yes 870
. 4200 Carcinogenicity ( Rat ) Ye s Yes Carcinogenicity (Mo use) Ye s Yes 870.5100 Bacterial Reverse Mutation Te st Ye s Yes 870.5300 in vitro Mammalian Cell Gene Mutation Test Yes • Yes 870.5375 in vitr o Mammal i an Chromosome Aberra t ion Test Yes 870.5385 Mammalian Bone Marrow Chromosomal Aberration Te s t Yes• No 870.5395 Mammalian Ervthrocyte Micronucleus Test Yes Delayed Neurotoxicity of Organophosphoms S ub s tanc es (A cute. I le n ) C R No 870 .6 100 Delayed Neurotoxicity of Organophosphorus Substance s (28 -Da y. Hen ) C R No Neurotoxicity Screening Banery ( Acute. Rat ) Yes 

# I Ye s 870.6200 Neurotoxicity Sc reenin g Battery (90- Day. Rat) Yes Ye s 870.6300 Developmental Neurotoxicity Study CR No 870 .7200 Compa nion Animal Safety C R No 870.7485 Metabolism and Ph am1acokinet ic s Ye s Yes 870
. 7600 Dermal Penetra t ion C R Yes 870 .7 800 lmmunotoxicit y Yes Yes



### .. C R
- Co n d111ona ll y ReqUired. NA = Not Applicable
. a Either g uideline st ud y t ype may be used to sa ti sfy the data requirement (e.g. 870 .5300 or 870.5375)
. b Study requirement waived (TXR0056649. K . Rury . 05 / 06 1 2013)
. c Study requirement waived (TX R0053424. S. Dap son. 11 113/ 2006)
. 

### Page 20 of26 Satisfied Yes Ye s Yes Yes Ye s Yes Yes Yes Yes NA Ye sb Yes Ye s Ye s Ye s Ye s Ye s Ye s Yes Yes NA NA Ye s Ye s Ye s' NA Ye s NA Ye s

### Att ac hm e n t 6 T o x icity Profil e for T riti c on azo l c Ac ut e Toxi c i ty ofT rit ico n azo le Tec hni ca l Guide l ine Study Ty p e MRIDNo. Results Tox icity No. Cate g ory 870.1 100 Acute Oral Toxicity 44802028

**LD ~o;:::**  2000 mg / kg Ill 44802029 LDso > 2000 mg!kg 870.1200 Acu t e Dennal Tox i ciry 44802030 LD so:::: 2000 mg!kg Il l 870.1300 Acu t e I nhalat i on 4 4802031 LC so > 2.63 rng/L I V Tox i city Non-irritant Acute Ocular Irri t ation I ndex : 2.7 Mean Ocular I rr it ati on I ndex: 0 870
. 2-WO Acute E ye Irritation 44802032 Transient redness to the conjunctivae at IV o ne hour aft er adminis t rat i o n in all animals; redness disappeared after 24 hou r s 870.2500 Acute Dcm1al 44802033 Not an i r ri t

ant IV I rri t ati on 870.2600 De rm a l Sensitizati on · 1 68 1730 1 Not a sensi tize r in th e 13ueh ler t est in N / A guinea pigs



### Page 21 of26Tox.ieity Profile ofT ri tieonazo le Tec hn ical G uid e line S tu dy Type MRID (year) I Doses I R es ults C las si fication 870.3100 90-Day Ora l 44802 102 (199 1) NOAEL (mglk gld ay): M = 2.0 F = Toxicity in 44802101 ( 1 99 1) 22.3 Rod e nt s D ietary Concentration ( ppm): LOAEL (m glkg/ day ): M = 19.8 

### F = ( Rat) 0. 25. 250. 12 500. 25000 1183.5 D ietary Dose ( mglkg/day): M: Ba sed on a s tat i s ti call y significant M : 0. 2.0. 19 .8. 1117.0.2309 .3 inc rease i n the i ncidence of adrenocortical F: 0. 2.2 . 22.3. 118 3.5 . 236 8.8 fatly vacu olation
. Accep tab le I Gu id e lin e F: Based on h ai r loss. decreased food efficiencies. adrenocortical fatly vacuolation. zona rc t iculari s degeneration. ccn tr inc in a r hcpa tocytic fatty vacuola t ion
. and more severe anisocyto sis and sphe rocytos i s. 870.3150 90
- Day Oral NA Refer to MR ID 448021 03
- t he Chronic Toxicity in Non- T ox ic it y S tud y in Dogs (870.4 1 00) Rodent s 870
. 3200 21128-Da)' 44 9 3360 I ( 1997) Dermal Irritat ion Dermal Toxicit y Dermal Dose (mglk gt day) : NOAEL ( m g./ kg/day): M = 1000 F "' ( Rat ) M : 0, 100.300
. 1000 1000 F: 0. I 00. 300. 1000 LOAE L (mg l kgf day) : M > 1000 F > Acce ptable I G uidelin e 1000 Svs ternic NOAEL ( mglk g/ day) : M 

## = 1000 F = 1000 LOAEL (m gfkg/day): M > 1000 F > 1000 870.3465 90-Day NA Study requirement waived (TX R00 56649. 06 Inh a lation May 2013) Toxici tY 870.3700 P re nntal 44 80210 5 ( 1991 ) Materna l Developmental 4480210-1 ( 1990) OAEL (mglkg/dny) "" 200 Toxicity Study Gavage Dose ( rnglk g/ day ): LOAEL { m g./ k g/ day) = 1000 ( Rat ) F: 0
. 40
. 200.1000 Base d o n reduction in mea n body weig ht Acceptable I G uideline gain during G D 12-16. DeveloJ2mental NOAEL ( mglkgf day) = 200 LOAEL (mglkgf day) = 1000 Based o n a treatmen t-re lnted in creases in unilnteral and bi lateral s upemumerarv rib s .



### Page 22 of26Toxic i ty Profile ofT r iticonazo le Techn ica l Guideline Study Type Prenatal Developmental Toxici t y S tud y ( R

abbit)

870.3800 R ep roducti o n and Fertili ty Effect s ( R

at)

870.4100 C hr o ni c Toxic ity (Dog) MRID (year) I Doses I C las sificar ion 44802106 (1991) Gavage Do se (mglkg/day): F: 0. 5. 25. 50. 75 Acceptabl e I Guideline

4

4933604 ( 1993) Dietary Conce ntra tion (p pm ): 0 , 5
. 25. 750.5000 Dietary Do se (mglkg/day): M

o: 0, 0.25. 1. 25. 37.5, 250 Fo: 0. 0.25, 1.25. 37.5, 250 M1: 0. 0 .25. 1.25. 37.5. 250 F 1: 0. 0.25, 1.25. 37.5. 250 Acceptable I Guide lin e

4480 2 103 ( 199 3) Dietary Concentra tion (p p m): 0, l 00 , 200. 400 Dietary D ose ( rn glkglday) : M : 0, 2.5, 25, ! 50 F: 0. 2.5. 25. 150 Acceptable I Guideline



### Page 23 o1'26 Results Maternal NOAEL ( m glkg!d a y) = 25 LOAEL ( mglkg/ day ) 

### = 50 Based on decrea sed body weight gain afle r dosing ini ti ation. reduced food conswnp ti o n . and mortalit y, and th e mat ern a l t ox icity. Deve l o pm e ntal NOAEL (rnglkg/ da

y)

- 50 LOAEL (mglkglday) ; 75 Based o n cranial variations. abortion. and increased pr e - and pos t-implantation losses . Par e ntal NOAEL ( m g!kg/d ay): M = 37.5 F = 37
. 5 L

OA EL ( m g/kg!day): M "' 250 F = 250 Based on red u ced body weigh t s of the F o females and the F
. ma l es and females and microscopic lesion s in the adrenal glands of F

o and F 1ma le s a nd female s. R

eprod u c ti ve NOAE L (mglkg/day) : M = 37. 5 F = 37.5 LOAEL (m g/ kglday): M
- 250 F

**~** 250 Based on F o perinatal mort a li ty, dec reased fertility of th e F1 animals. Offspri ng NOAEL (mglkg/day): M = 37.5 F "' 37.5 LOA EL (mglkg/day): M "' 250 F = 250 Based on reduced F 1 ;md F 2 pup survival. and reduced F 1and

**~** pup body we i !!,ht NOAEL ( m glkg/day): M = 25 F 

### = 25 LOAEL (mglkglday): M = 1 50 F "' 150 Based o n dec r eased absolute body weights of female dog s. decreased weight gain by male and female dogs. and tr eatm e nt-r e lated t oxicity to t he eye. l iver. and ad r enals: in addi tion to transient n e urolog ical sig n s ( tremors , h) peroctivit) or hypoactivity. convulsions, and ata xia).Tox i city Pro fil e of T ritico nazo l e Techn ical G uid e lin e S tudy Ty pe 870.4200 Carcinogenic it y (Mouse)

870.4300 Combined

870.5 1 00

870.5300

870 .5375 Chronic Toxicity 1 Carcinogenicity ( Rat )

Bacterial Reverse Mutation Test (Salmo n ella 1_1

phimurium)

in l'itro Mammalian Cell Gene Mutation Test (C hin ese Hamster V79 Cell s) in vitro Mammalian C hromosome Aberration Te st (Human Lymphoc y tes) MRID (year) I Do ses I C lassi fi ca t ion 44802108 ( 1994) Dietary Conce ntrati on (ppm): 0. 15. 150. 15 00 Dietary Dose (mglkg lday): M: 0. 1.8 . 17.4. 202
. 2 F: 0. 2.1. 20
. 1. 209 .5 Acceptable I Guideline

44802107 (1994) Dietary Con ce ntrati on (ppm): 0.5.25. 75.5000 Die t ary Dose ( rn glkglday): M: 0. 0.2. 1.0. 29.4. 203.6 F : 0. 0.3. 1 .3. 38.3. 286.6 Acceptable I Guideline

44802109 (1991) Applied Dose ()Jg/plate): ± S9: 25. 79.250.790.2500 Accep ta b le I Guideline 44802 11 0 (1999) App li ed Dose ( )Jgl plate): ±S 9: I0.0. 33.3. I0. 333 Acceptable I Guideline 44807113 (1991) Applied Dose (mg/m L): ± S9: 62.5. 125.250. 500 Acceptable I Guide lin e
44802111 ( 1997) Applied Dose ( ppm ): ± S9: 274.4. 392. 560 -S9: 337.5. 450. 600 -'- $9: 253.1. 337.5. 450 Acceptable I Guideline



### Page 24 of26 R esults NOAEL (mglkg l day ) : M
- 17.4 F
- 20. 1 LOAEL (mglkglday): M == 202.2 F = 209.5 Based on decreased body weight gain and liver toxic it y (e .g. hepa t ocytic large fatty vacuolation). Treatment for up to 78 weeks with RPA400727 did not r esult in a s ignificant increase in the incidence of neoplastic lesions in this stud y. NOAEL ( mglkg/da y): M 

### = 203.6 F - 38.3 LOAEL (mg/kg/day): M > 203.6 F = 286.6 F: Based on decreas ed body weight and body weight gain and adrenal conical and liver toxicity ( e.g. fatty vacuolation). RPA400727 showed no carcinoge n ic activity in either male o r female rats after ad ministration for up to I 00 weeks. No evidence of compound-induced car cinogenicity as per CARC repon June 15. 2006). -±- S9: Negati ve up to 2500

**~tg/plate.** TI1erc was no evidence of treatment-induced mutant colonies above background level s.
::: S9: Negative up to 2500

**~t g/**  **plate.** The r e was n o evidence of treatment-induced mutant colonies above backg r ound levels
. There was no consi s tent evidence of induced mutant colonies over background.

A Ithough there was s ugges t ive evidence of a possible increase in the frequency of aberrant cells at cy tot oxic doses in the absence of 59
- mix. the po si tive re su lt s were not n:produciblc: therefo r e there was no consistent evidence of chromosomal aberrations induced over background.Tox icity Profil e ofTriticooazole Tec hn ical Guideline Study Type MRID (year) I Doses I Res ul ts Classificatio n 870 .53 95 Mammalian 44802114 ( 1992) There was no s ignificant increase in the Erythrocyte Gav age Dose (mgtl:g): frequency of m icronucleated polychromatic Micronuc l eus M: 0, 25, 125 , 625 erythrocytes in bone marrow after any tested Test (Mo use) F: 0.25,125 .625 RPA 400727 do se a t an) harvest time. Acceptab l e I Guideline 870.5550 U n sched ule d 44802112 ( 1992) There was no evidence that unscheduled DNA Syn th esis Dose ( J.l g/ rnL) : DNA synthesis
. as determined by radioactive in M am mali an 7.81, 1 5.6, 31.3.62.5 trac er procedures [nuclear silver grain Cells in Culture Acceptable I Guideline counts] was induced. (Ra t Hepnt ocytcs) 870.6200 Acute 44802036 ( 1997 ) Neu r otoxicity Neurotoxicity 44933602 ( 1997) NOAEL (mg/kg): M = 400 

### F
- 400 Screening Battery Gavage Do se (mglkg): LOAEL ( m g/ k g) : M = 2000 F = ( Rat) M: 0. 80, 400. 2000 2000 F: 0 , 80,400.2000 Based on increased motor activity in both Acceptable I Guideline males and females. Svstemic NOAEL (mglkg/day) : M = 1000 F = 1000 LOAEL ( m glkg/ day ): M > 1000 F > 1000 90-Day 44933603 ( 199 7) Neurotoxicitv / Svstemic Neurotoxicity Dietary Concentrati on (ppm): NOAEL (mglkglday): M
- 695.1

**~** Screening Bancry 0. 500, 2500. I0000 820.3 ( Rat ) Dietary Do se ( mglk g/day): LOA EL ( mglk g/ day): M > 695.1 F > M: 0 , 32.5, 169.9. 695. 1 820.3 F: 0. 38.5. 199.4. 820.3 Acceptable I G uid e line 870.6300 Dev e lopmental 4655050 I (2005) Study requi r ement waived (TXR0053424. 13 

# I Neurotoxicity Waiver Reque s t Novembe r 2006 ) S t

ud y



### Page 25 of26Toxici ty Pro fil e ofTriticooazo le Techn ica l Guide line Study Type 870.7485 Me t abo l i s m an d Pham 1acokineti c s ( Rat )

870.7600 D erma l Penetrati o n ( Rat )
870.7800 lmmun o t oxici t y ( R

at) MRrD (year) I Do ses I Class i fication 4650340 I ( 199 3) Gav age Dose ( mg/kg): Si n g le : 5 . 500 R

epeated: 5 ( 14 Day s) Acce ptabl e I Guideline 47 15 89 0 1 (2000) Bi li ar y Excretion Gavage D ose (mglkg): S in g l e: 5 . 500 Accept able I Guidel in e

44802115 (1996) De rmal Dose (m g/ cm 2 ): M: 0.15.3 Acce ptable I Guideline 48 733901 (20 11 ) Diet ary Concentrat io n (ppm): 0.500.1500.5000 Diet ary Dose (mglkglday): F: 0. 53. 16 2. 462 Acceptab le I Gu ide lin e Results Ab sorptio n o f an oral dose of tritic onazole was rapid and r eac hed its peak b lood concentration between 1 and 2 hour s after dosing. In th e hig h do se (500 mglkg ). RPA tr iticonazolc was found in th e greate s t co ncentra ti o n in th e li ve r. kidneys. lungs. fat. Gl t ract. skin/fur. blood and plasma. A lso . it wa s found in mal e hea n s and in female uteri
. TI1e te s t compound was me t abol ized rapidly. since l eve ls of parent co m pou nd (0.1 7 -1.44 % AD) were significantl y lower than metabo lit es ( 14-4 I % A D) after 24 hours. TI 1 c mo s t abu n dant metabo l i te in the urin e was RPA 406972 (45
- 65% AD) in the 500 mg./kg dose and a hyd r oxylated RPA 406972 (29
- 33% AD) in th e 5 m g/

kg dose. The mo s t abundant components found in th e feces were RPA 406972 an d RP A 405826/4 0488 6. RPA 40072 7 i s primarily eliminated through bili ary excre ti o n . Excre ti on wa s rapid. m ost of th e radiolabel being exc ret e d in th e ur ine and feces with in 48 hours of t rea tm ent ( > 90 % for th e s ingl e -do se groups: > 67 % for the repea t-d ose groups). Dermal Absorptio n Factor = 2% Based o n th e da t a presen ted in th e r ev iewed study dermal absorp ti o n of th e te st material is minim al ( <2% of the administered do se) at th e l ow and

**hi~h** dose. lmmunotoxicitv NOAEL (mg/k gl day ): M = NA LOAEL ( mg.lkg.l day ) : M = NA Svste mi c F = 462 F > -162 NOAEL (mglkglday): M = NA F = 1 62 LOAEL (mglkg/ day) : M = 1 A F - -162 Ba sed on r ed uced body weights and body

.._ _ _ _ ......._ _ _ _ ___ _,__ _ _ ___ ___ _ _ **___._ _ve**  **igh t**  ga in s. and increased liver wei c hts.



### Pa ge 26 o f 26