### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , 

### D.C

. 20460 OFFICE O F CHEMICAL SAFETY AND PO LL UTI O N PREVENTI O N 

### M EM ORAND UM DATE: July 20, 2015 

### SUBJECT: Bromucon az ol e. Hum an Health Scoping Document in Support of Registration Review.



### P C Co de : 120503 

### Deci s io n No

. : 504955 

### Petition No.: N A 

### DP Barcode: D427265 

### Reg i s tration No.: NA Reg ulato ry Action: Registration R eview Scoping D oc um ent 

### Ri s k Assess ment Type: NA TXRN o.: NA C as e N o.: 7035 

### CAS No.: 116 255 -48-2 40 CFR: NA 

### MRI D 

### No . : NA F ROM:

THRO UG H :



### TO : Barry O ' Keefe , Senior Biologist Vincent Chen , Toxicolog i st Risk Assessment Branch III (RAB3) Hea lth Effec t s Division (7509 P) Office of Pesticid e Program s Chr istine Olinger, Branch C hi ef 

# /J/ / ';// ' Risk Assessment Branch Ill

## (RAB~ 

# f-/- (__ Health Effects Division (7509P) Office of Pesticide Pro grams James Parker , Chemical Review Manager Tom Mori arty, T ea m Leader Ne il Anderson, Branch Chief Risk Management and Impl eme nt at ion Branch I ( RMIB I ) 

### Pesticide Re-Evaluation Di vis ion (P RD ) (7508P) Office of Pesticide Pro g ram s 

### Exec utive S umma ry Following is the Health Effec ts Divisio n 's ( HED 's) human health scop ing document for the fungicide bromuconazole to support R eg istration Re view. To eva lu ate the scope of work necessary to support Registration Review , HED has considered previous ri sk assessments for bromuconazole: updates to its toxicity , exposure. and usage databases ; and th e latest Agency science policy and risk assessment methodologies. The only risk assessment for bromuconazole was conducted in 2002 (028 174 5. J. Arthur. 09118 / 2002). That assessment was for occupational exposures, wh ich are the only ru1ticipated ex posures from th e sole registe r ed u se of
Page I 

### of 18

### bromuconazole o n roses , g r own commercially in greenhouses, to control b l ack spot growth. There are no residential uses. The toxicology database is adequate for risk assessment. In repeated dose studies the most consistent ly observed effects of bromuconazole across species, sexes , and treatment durations was liv er toxicity . Th ere is no ev idence of increased susceptibity following 

### in utero exposure in a dermal developmental toxicity study in rats or followi n g oral exposure to rabbits. There is no evidence of increased susceptibity following pre/ post-natal exposure to rats. There is no concern fo r the increased susceptibi lity seen following oral exposure to rabbits , si nc e there are no fooduses and thus no potential for dietary exposure by humans. Bromuconazole is classified as " not likely to be carcinogenic to humans.'· Bromuconazole did not cause mutagenicity or genotoxicity. There arc no neurotoxicity o r immun otoxicity concerns with respect to bromuconazole. Dermal abso rption has not been determined. New occupation a l handler and post-application expos ure and ri sk assessments will be needed during Registration Review because policies on body weights and unit exposure values and assumptions have changed s inc e the initial assessment. Also, the label (E PA Reg. No. 264

- 548) needs to be amended to include a 12 hour re-entry interval (REI), based on the acute toxicity of the technical grade of the active in gredient bromuconazole. 

### Introduction Bromuconazole , a triazole that belongs to the demethylation-inhibitor fungicide group , blocks black spot growth by disrupting membrane formation through inhibitin g the sterol biosynthesis pathway at the enzyme erg I l / cyp5 I. There are no mammalian molecular data to specifically demonstrate a mode of action in test an im als

. There is only one re g istered end us e product (E PA Reg. No. 264-548), an emulsifiab le concentrate. Th e only human health risk assessment for bromuconazole was comp leted in 2002 (0281745, J. Arthur, 09 / 18/2002)

. That assessment was for occupational exposures , which arc th e only anticipated exposures from the sole registered use of bromuconazole on roses in greenhouses. Refer to Attachment 1 ( Tabl e 1 ) for the chemical identity of bromuconazole. 

### Hazard Id e ntification/Toxicology The studies available fo r risk assessment include an acute toxicity battery; subchronic oral toxicity studies in rats , mice and dogs; a subch roni c dermal toxicity study in rabbits ; chronic toxicity studies in rats and dogs ; carcinogenicity studies in rats and mice; prenatal developmental toxicity stud i es in rats and rabbits; a reproduction and fertility effects study in rats; a battery of mutagenicity and genotoxicity studies; and a metabolism and pharmacokinetic study in rats. Based on a metabolism studies in rats, bromuconazole is well absorbed , extensively metabolized , and rapidly elimi nated. Following th e administration of ora l doses to rat s for fourteen days, 95

- 102% of bromuconazole was recovered. Females excreted higher levels than males via urine, but males excreted more in their feces.

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### The most consiste ntl y observ ed e ffects of bromuconazole across species , sexes, and treatment d urati o n s was li ve r toxicity. In the rat, mouse , and dog repeat do se oral toxicity s tudie s, th e liver effects were manif ested by in creased li ver weight and increase d incid ences o f li ve r pathology ( i. e., hepatocyti c fatty vacuo l ation and hepat ocyt ic de ge neration ). Liver effects we r e also obse rved in the rat de rmal prenatal deve lopme nt a l toxicity s tud y ( i. e. , in c reased mate rnal liver we ig hts ) and th e reproduction and ferti li ty effects stud y (i.e., increa se d pare ntal li ver weights and increa se d inc id ences o f h epatocytic fatty 

### vacuo lation )

. The database contain ed an ora l a nd a dermal d eve lopment a l toxicity studies in rats. In th e oral d evelopmental stu dy, there was ev idence fo r increased suscept ibility; d evelopment al effect s (i.e. , additio nal cervica l ribs and increase d placental weights) oc curre d a t a do se lower than the do se that caused maternal tox ici ty ( i .e. , decreased body we ig ht gain, and increase d li ve r weights). Jn the d e rmal devel o pm e ntal toxic ity study, there was no evidenc e of in creased s u s ceptibilit y; de ve lopmental effects ( i.e. , ad diti onal ribs) occurred at the same d ose a s the dose that cau se d maternal toxic ity ( i. e . , ungroom e d and unke mpt coat). In the ra t reprodu c tion an d fe rtili ty effects s tudy, offspr in g toxicity was m an i fes t as decreased pup viab ility and d ec r ease d pup body weight gai n at the same dose as parental toxicity (i.e., decreased body we i g ht gain , in c rea sed liver weights, and increased incid e nces of he patocyti c fatty vacuo l ation). In rabbits , there we re no ind ic ations of reproductive s u sceptibility 

### in utero. Overall , there are no res idu a l uncertainty for p re/ po s t-nat a l toxicity ; th e re i s no concern fo r the in creased suscept ibility see n in the oral d evelop m e ntal study , s in ce there are no food -u se ( i .e no tolerance es tab li shed) and therefo re no potential for hum an di e tary exp os ur e. Bromuconazo le is classified a s " not likel y to b e carcinogen ic to human s " based on the l ack of evide nce for carcinogenicity in mice a nd rats
. Bromuconazole did no t cause muta ge nicity or genotoxic ity in 

### in vitro and 

### in vivo assays. In the rabbit prenatal developmental toxicity study, maternal animals expressed c li nical s i g n s of toxicity that may indi cate ne urob e havioral effects such a s: leth argy / re lu ctance to m ove , increase d re s piration rate , ataxic/ unsteady gait, aggression , lack o f muscle tone and c oordinati o n , prone posture , and vocalization. How eve r , the Agency waived the acute and subchronic ne urotox icity stu di es s in ce there are no dietary o r ora l exposu r e sce nari os (TX R00 57274, 25 Jun e 20 1 5)

. The Agency wa i ved the s ub c hro nic inhalation s tud y because th e inh a lation margin of exposure (M O E) is greater than the Age ncy's l evel of concern for inhalation waive r s(> 1000) (TX R0057274, 25 Jun e 2015)

. The Agency waived th e immunoto x icity s tud y fo r th e fo ll ow in g reaso n s: ( 1) th e re was no ev idence of adverse effects on th e immun e system in mice. rats , o r dogs in the data base for a ny of th e co n azo le pesticides ; (2) the li ve r, n ot the immune sys tem. is genera ll y the target o rgan for this chemica l cl ass , and hepatotoxicity or body weight changes a re th e primary toxicological e ndp o in ts of concern and were u sed in ri sk assess me nt s; (3) th e co nazo les d o no t be lo ng to a 

### class of c h em ic als 

### (e.g., the organotins, heavy metals , or halo ge nated aromatic hydrocarbon s) that wou ld be expected to be immun otox ic

. There was n o ev id e nc e of im mun otoxic ity with s ix
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### other s tru c tur a ll y -r e lated conazole fungicides , namely , flutriafol , metco nazo le , tebucon azo le , te traco n azo le , tri adim efo n , triflumi zole , and tritic o naz ole

. In th e immunotoxicity s tud y fo r triflumi zo l e , the effects on the immun e system occ urred on l y at the highe st do se te s ted. Immunotoxic ity was demonstrated wit h difenoconazole , howeve r it was o b se r ved in th e pre se nc e of sys temic tox ic ity and at a relativ e ly hi g h d ose ; and (4) P O D s based on th e most se n s iti ve endpoi nt s ob tai ned via the app ropriate routes o f exposure in the most sensiti ve s pecies are c urren tl y u sed for dietary a nd no n-di eta r y ri s k assessments (TXR00 5 7274 , 25 June 2 01 5)

. Bromuc o naz o le has lo w to mod e rate toxicity via the oral (T oxic ity Category lI ), de rma l (Toxicity Category III ) , and inh a lati o n (Tox ic ity Category IV ) routes ; is a s li g ht eye irrit ant (Tox icit y Catego ry IJI ) 

### and is n ot a dermal iITitant (Toxicity Categor y IV ); and is not a dem1al se n s itize r. Plea se refer to Attachment 3 for a summary of the toxicity en dp o int s a nd POD s for bromuconazo l e, a nd to Att ac hm e nt 4 for the complete toxicity profil e tabl es fo r bromu co n azo le. Concl u sions: Th e toxico logy database for bromuconazole is adequate for risk assessment of the current u ses. At th e time of Reg istration Revi ew o r th e ne xt ri sk assessment , the Agency will upd ate POD s and endpoi nt s si n ce the y are base d o n to x icological effects that th e A ge n cy no lon ge r co nsid e rs adve rse. Additiona ll y, th e uncerta inty factors will b e re- assesse d in th e context of th e updated POOs a nd en dp o in ts. 

### Di et ary E xp os ure Ba sed on th e so le use of bromuconazole o n roses in greenhouses , di e tary ex po s ure is no t expec ted , and therefore, do es not need to be assessed durin g R egistrati on Re view

. 

### R es identi a l Ex posure Ba sed on th e so le use of bromuconazo le o n roses in greenhouses , r es idential expos ure s are no t exp ec ted , and th e r efo re, d o not nee d to b e assessed during Regi s trati o n R ev i ew. Ad diti ona ll y, the potential for res id e ntial exposur es from spray d rift o r bys tander ex po s ure are not expected , s in ce th e u se is confined to gree nhou ses o nl y. 

### Aggregate Risk Assess m ent Aggregate a sse ssment s consider exposures from food, drink ing water , and re side nti al u ses . S in ce there a re no re side nti a l u s es of bromuconazole , nor are there any u ses that would res ult in expos ures from foo d or drinkin g water , a n a gg re ga te ri s k a ssess ment is no t req uired during Re g i stration Review. 

### Occupationa l Ex po s ure Bromuconazo l e is re g is tere d for us e on roses grown in greenhouses. There is potential for s hort- ' inte rm ed ia t e - , and long -term occ up ational exposure t o bromuconazo le durin g handlin g ( mi x in g , load i ng , and app ly in g) and post-application activities in greenhouses.

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### Occupation a l H an dl ers The registered bromuconazole label re quires occ upational handler s lo wear l o ng - s l eeved s hirt s, long pant s, shoes , socks, and waterproo f g loves. The previous occ upati o nal handl e r exp os ure an d ri sk assessment ( D 2 81745 , J. Arthur, 09 / 18/ 2002) was conducted at the maximum application rate and ass.u rn ed the maxi mum area treated p e r da y . The risk estimates from dermal and inhalation expos ures we re combined because the PO D was the same for both routes and was based o n the same to x icolo g ical effec t s ( i. e., skeletal effects). The s hort- and intermediate-t e rm risk esti mat es for dermal and inh a lati o n exposures of occu p ation al handlers at baseline attire did not exceed the l eve l of concern ( LOC) for a ll combined d e rm a l and inh alation ( i.e

.. MOEs < 100) sce narios. Occupati ona l Post-App lic ation Occupational post -applic atio n short- and intermediate-term dermal and inhalation exposures are possible for wo rke rs e nterin g g r ee nh o use s to te nd to or h a r ves t treated roses. C hemical- s pecific post

- app li catio n ex p osure data h ave not been sub mi tted

. The most recent post-app li cat ion assessme nt for bromuconazole was completed in 2002 (028 1745, 

### J. Arthur , 09/18 / 2002) which u se d th e default dislodgeable foliar residue ( D FR) fraction of app l icati on rate ( F AR) value (20%). At th at tim e , th e re s ultin g MO Es ranged from 4 70 to 4, l 00 for th e currently registered u se on roses at the maximum rate (0.02 lb ai/100 gallon at 200 ga ll o n s of spray/ A), and did no t exceed HED 's leve l of concern (LOC) of I 

### 00 ( MO E< LOC). The c urrent d efault FA R va lu e for post-application act ivi ti es is 25%. W ith th e use of the cu rrent F AR valu e , as well as updated tr an sfer coefficient (TC) va lu es and adult bod y weights , th e resulting highest exposure risk esti m ate for p os t- application exposure from the app li catio n to roses at th e maximum rate r es ult s in an MOE of 1 ,500

. Si nce the hi g hes t estimated occupational post-app li cati on exposure using default D F R and TC va lu es for bromuconazole is minimal in comparison to th e lev el of concern ( i .e., the calculated MOE i s greate r than 2 times hi g her than the level of concern, MOE > 200 compared to the LOC of I 

### 00) , H ED is not req uirin g the 40 CF R 

### § 158 DFR data. T h e C HIPCO ® Bromuconazole la b e l ( EP A Reg. No. 264-548) does not currently have a restricted

- e ntry interval (RE I) li s t e d on th e label ; in s t ead it s tates a s follows: " Do n ot enter o r allow others to enter the treated area until sprays h ave dried:· The RE I specified on the reg i s t ered label s hould be based on th e acute toxicity of th e act ive ingredient bromuconazole. Bromuconazole is classified as Tox icity Catego ry III via the dermal route and eye irritation , and T ox icity Catego r y IV fo r ski n irritati o n potential. It 

### i s no t a sk in sens iti ze r. Under 40 CF R 156.208 (c) (2) (iii), active in gred i ents cla ss ifi ed as Ac ut e Toxi c ity Catego ry III or J V for acute de rm al, eye irritation and primary ski n irritation are ass ig ned a I 2 -h our REI. Ther efo re , the [I 56 subpart K] Worker Protection Stateme nt ( WP S) inte rim RE I of I 2 h o urs is adequate to protect agricu l tural wo rkers from post-app li cat ion exposur es to bromu co n azo le . 

### Conclusions: Th ere is sufficient in formation available to assess occ upati o nal handl er an d po s ta pplic at ion ex po s ure s of bro muc o n azo le , so no ad diti ona l data wi ll be neede d in r eg i s t rat ion review. During Registration R ev i ew a new assess m e n t of occ up ational h a ndler and po s tapp li cation exposu re s w ill be needed because the most recent assess ment was co ndu c ted several
Page 5of18

### years ago , and policie s and data inputs and assumptions h ave c h anged. A lso, HED ha s s inc e updated it s policy o n body weights a nd update d unit exposure valu es, and o th er input s (e

. g . , uncertainty facto rs, to x ici ty e ndp o int s, or points of departure) for determining these risk estimates. These c han ges are not expected to result in risk es timates that wou l d req uire 40 CFR 

### § 1 58 DFR d a ta. A lso, the l abel (E P A Reg. No. 264 -548 ) needs to be am ended to includ e a 12 hour RE L 

### P ublic H e alth a nd P es ti c id e E pid e mi ol ogy Data There we r e no in ci dent cases r e porte d for bromuconazole in both th e OPP In c id e nt Data System ( ID S) and th e Centers fo r Disea se Co ntrol and Preve nti on/National In stitute for Occupational Safety and H ea lth (CDC/N IO S H ) Senti nel Event Notificatio n System for Occupati o nal Ri skPes ti c id cs (SENSO R)

. There d oes no t appear to be a concern at thi s tim e that wou ld warrant further investigat io n . For the Main IDS , from Jan u ary I , 20 1 0 to February 5, 20 15, there were no incidents reported invo lv in g bromuconazole. In the Aggregate ID S, from January I , 2010 to February 5 , 2015, t h ere were no incidents rep o rted involvin g bromuconazole. A query of the SENSOR-Pesticides database fo r 1998-2011 iden tifi es no cases involving bromuco n azo l e. The Agri cul tural Health Study ( AH S) is a high quality , prospective ep id e miol ogy st ud y eva luatin g the li nk b e twee n p es ticid e u se an d vari o us health o ut co m es, including cancer. Th e AHS include s private and commercial pestic id e appl icators and their spouses. Bromuconazole

- i s not included in the A H S, an d therefore , thi s s tud y does not provide informati o n for this rep ort. 

### Conclusion: T here we re no inc ident cases reported fo r bromuconazole to e i ther ID S o r SENSO R-P es ticid es; th e refo re, th e re does no t appear to b e a concern at thi s time that wo ul d warrant further investigation. The Agency w ill co nti nue to monitor the inc ident inforn1ation and if a co ncern is triggered, additional anal ys i s wi ll b e includ ed in th e ri s k assessment. 

### T o le ra n ce Asses s m e nt a nd Inte rn ati o n a l H a rm o niz ati o n T h ere are no ex isting tolerances for bromuconazo le, and therefore, no assessme nt i s needed. 

### C umul ative Bromuc o n azole is a member of the triazo le-co nta i ning class of pesticides. A lthou g h conazoles ac t s imil ar ly in plants (fu n g i) by inhibiting ergostero l biosynthesis, there i s not nec essaril y a relation s hip betwee n the ir pesticidal activ i ty and their mechanism of toxicity in m amma l s. Struc tura l s imi larit ies do no t constitute a common me c hani s m of to x ic ity. Evide nce i s needed to es tablis h that the che mi cals ope rate by the same, o r essentia ll y the same, se qu e nce of major biochemica l eve n ts. In conazo les, however , a var iab le pattern of toxicol og ical re s pon ses is

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### found; some are hepatotoxic and hep atoca rci no gen ic in mic e. Some induce thyroid tumors in rats. Some induce deve lopmental , reproductive. and neurological effec t s in rodents. Furthermore, the conazoles produce a diverse range of biochemical events in c ludin g altered cholesterol l evels, stress respo n ses, and altered DNA methylat ion. It is not clearly understood whether these biochemical events are d irec tly connected to th e ir toxicological outcomes. Thu s, there is currently no evi dence to indicate that conazoles share common mechanism s of toxicity and E PA is not following a cumulative ri sk approach based o n a common mechani s m of toxicity for the conazoles. For information r egarding EP A's procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA's website at http: //www.epa.gov/ pesticides/ c umulativ e. H um an S tudies The risk assessme nt s which have been previously conducted for bromuconazole reli ed in part on data from st udi es in which adult human subjects we re intentionally exposed to a pe s ticide to determine their dermal and inhalation exposure. Many such studies , in volving exposure to many different pesticides, comprise generic pesticide ex posure database s such as the Pesticide Handlers Exposure Database (PHED ) and the Agric ultural Reentry Task Force (ART F) Database. EPA has reviewed all the stud ie s supporting these multi-pesticide ge neric exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly d efi cient relative to the ethica l standards prevailing at the time the research was conducted. All applicable requirements of EPA 's Rule for the Protection of Hum an Subjects of Re sea rch (40 CF R Part 26) have been sat is fied , and there is no regulatory barrier to con tinued rel iance on these studies. Data Deficiencies None

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### Ref e rence s Mem o r a n da Re lev ant t o R el! is tr atio n Revi ew of Cvc loate.

Aut h o r OPffXR# D a t e Titl e Ris k As sess me nt J. Arthur D28 1745 09118/ 2002 Bromuconazole: Occupational and R esidential Ri sk Assessment of a New Fungicide fo r Use On Ro ses. T oxico logy M

. Bonner TXR 09 / 04/ 2003 BROMUCONAZOLE (PC Code 120503)

- Toxico logy Disciplinary 0051892 Chapter for Reg is tration Sup port Document for Use on Roses. U

. Habiba TXR 08 / 13/ 2013 CONAZOLE FUNGICID ES: Summary of H azard and Science Policy 0056730 Council (HASPOC) Meeting on Jul y 25 , 2013: Recommendations on Data Requirement for lmmunot oxiciry Studies for Conazole Pe s ticide s. U. Habiba TXR 06/25/ 2015 Summary of Hazard and Science P olicy Council (HASPOC) Meeting 0057274 of Jun e 25 , 20 15: R eco mm endations on th e Need for a S ub chro ni c Inh alation Toxicity Study and a Neurotoxiciry Banery (Acute and S u

bchronic). In c id e nt Report S. Recore D427797 06/ 16 / 2015 Br o muconazole: Tier I R ev iew of Hum an In c idents 

### Attachments 1. Chemical Identity Table 2

. 

### Physicochemical Properties of Technical Grad e Bromuconazole Table 

### 3. Endpoint Se l ection Table 4. 

### Toxicity Profile Tab les 5

. Tox ico lo gy Data Req uireme nts Table

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### Attachment 1 Chem i cal Identity T a b l e Table 1. 

### Bromuconazole Chemical Structure. - Common Name (Abbreviation) 

### Structure Chemi cal Name

B r o mu conazole 

# ·-<iV" 1-[[4-bromo- 2

-(2,4 -di c hlorophen y l)tetrahydro- 2- furanyl]methyl] -1 H-1 ,2,4 -triazole 

# r ( N 'N N_J



### Page 9of 1 8

### Atta c hment 2
T a ble 2 . Ph vs ic oc hemi ca l Proper ties of th e Technic a l Grade Test C ompound • P

a ra me te r Va lu e Co lor White Physical S tate Solid Odor S lightly alcoholic Storage Stability Stable pll 5.3 Melting Point 84 °C Density 1 .721?/ml LS850646 LS850647 Ace tone 3 1. 86 g/ 100 ml 2 1. 97 g/ 100 ml Di chlo ro meth ane 49 .7 g/ 1 00 ml 35.37 g/ 10 0 ml Ethyl Acetate 23

. 19 g/ 10 0 ml 17.30 g/ 100 ml N

- 1 lcxa ne 0. 165 g/ 100 ml 0. 1 92 g/ 100 ml Solubility Methanol 29

. 54 g/ 100 ml 18

. 85 g/ 1 00 ml 1-0 ctano l 6.14 g/ 100 ml 3.85 g/ 1 00 ml 2

- Propano l 5.74 g/ 100 ml 3

. 9 8 g/ 1 00 ml Toluene 2 1. 72 g/ 100 ml 15.68 g/ 1 00 ml Wat er ( Di stilled) 60.9 mg/I 20.8 m g/I Water ( pH 5 ) 52 .3 m g/

I 17.0 mg/I Wate r (p H 9) 59.4 ml!.1 1 22. 1 m g/I

. 

### . 1 Pc s 11c1de Fact S heet for Bromuconazolc , Nove mber 2002

.



### P age 10of 1 8

### Attachment 3 S umma ry of Toxicity E ndpoint s and Points of Departure of Bromuconazole
T a b le 3: S umm a ry ofToxico logical Do ses an d Endp o in ts for use in Occupational Hum a n H ealth Risk Assessments Point of U n certai nty I RID, PAD , Level Exposure Scenario Departure (Po D ) FQPA Safety of Co nce rn fo r St ud y a nd T ox ico logica l E ff ects Factors Ri s k As s essment Dermal Developmental UFA = lOx Occupational LOC Prenatal Develo[lmcntal Toxicitv

- Shon Term Dermal OAEL = UF11 = IOx for MOE = 100 Rat ( 1- 30 days) 4 0 m g/kg/day Developmental Derma l LOA EL= 1 33 m g/

kg/day Int ermediate Term Based on increased incidences of ( 1-6 months) s keletal a nomalies (i.e

.. extra ribs). In ha l ation Dev e lopmental UF" = ! Ox Occupati onal LO C Prenatal Dcvelo[lmcntal Toxicitv

- Short Term NOAEL= UF11 = ! Ox fo r MO E = 100 Rat ( 1- 30 days) 10 mg/kg Developmental LOAEL = 70 m

g/kg/day Intermediate Term Nole : Toxici 1 y via B ased o n increa se d incidence s of (1-6 months) the i11halatio11 and additional cervical rib s. oral routes are assumed 10 be equivalent for thi s scenario
. Cancer (o ral. Classificati on: ·•Not Likely to be Carcinogenic to I lumans·· based on both the lack of carcinogenicity dermal. and in mice and rat s. inhalation) Pomt of Departure ( PoD ) = A data point o r an est im ated pomt that rs derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOA EL = no observed adverse effec t level. LOAEL = lowest observed adverse effect level. UF = uncenainty facto r. UF" = ex trapo lati on from ani ma l to human (interspec i es). UF11 = potential variation in se ns itivity amon g m embe r s of th e hum a n popul a ti on ( in traspc cics). FQPA SF = FQP J\ Safe ty Fact or . MOE

... margin ofexposure. LOC = level ofconcern. N /A = not ap plicable

.



### Page 11of18

### Att ac hm e nt 4 Toxicity Profil e for Bromu c ona z o le
Ta b le 4. 1. A c ut e To x i ci t y D ata o n T ec hni ca l Bro mu co n azo le. Gu id e l i n e Study Type MRJD No.&% R es ul ts T ox i c ity No. Active ln l! r ed i e nt Catel!orv 870.1100 Acute Ora l

- Rat 42937 1 2 1 LD so = 365 mg/kg (Males & Females, II 95.7% " combined) 870

. 12 00 Acute Der m al

- Rabbit 42937 1 22 LD so > 2000 mg/k g ( Male s & Females. 111 97.8 b combined) 870. 13 00 Acute Inh a lation

- Rat 42937123 LC so > 5.05 mg/L (Males & Females. IV 98.4% combined) 870.2400 Primary Eye Irrit ation

- Rabbit ·BO l85 01 0

. 1 ml. Mild Irrit ant 111 95.7% 870

. 2500 Prim ary Skin Irrit ation

- Rabbit 430 18 502 Not an Irritant IV 95.7% 430 18 503 Not a Dermal Sensi ti zer. NA 870.2600 Derm al Sensitization

- Guinea Pi g 95.7% • l3romucona1ole Tech

. Used in these s tudie s i s al so kn own as LS860263 which is made or 1wo i so mers wi1h 1he ra1io of 55

. 5

-56

. 5% LS850646 & -12

. 9-43.5 % LS85 0647

. • Isomer ra1io 1101 provided in the record s.

Ta bl e4.2. S u bc hr oo i c, C hro ni c a nd Ot h er Tox ici ty Pro fil es fo r Br om u co n azo le. Gu i de li ne 870.3100

870.3150 St ud y T y p e 90-Day Oral Toxicity in Rodents ( R at)

90

- Day Oral Toxicity in NonRodcnt s ( Dog) MRJD (year) I D oses I C lass ifi catio n 42937131 ( 1 990) Dietary Concentrat ion (ppm): 0.40

. 200. 1000. 5000 Dietary Do se (mg/kg/day): M: 0. 2. 72. 1 3.76. 68.1. 342

. 5 F: 0, 3.0-1, 15.08. 74.5. 381.2 Acceptable I Guideline -13 018505 ( 1988) Capsule Dose s (mg/kg/day): M: 0. 2.5. 25. 250 (-1 weeks) 125 (After 4 weeks) F: 0. 2.5. 25. 2 5 0 (4 week s) 125 (After 4 weeks) Acceptab le I Guide! inc



### Page 12of 18 R es u lts NOAEL (mg/kg/day): M 

## = 13 .8 F = 15

. 1 LO/\ E L (mg/kg/day): M 

## = 68

. 1 F 

## = 74.5 Based on decreased body \\eight gains in females. changes in hematology/b l ood c hemistry parameters and in the incidence of microscopic lesion s consisten1 with liver toxici1y. and increased liver wei!!ht in both sexes . NOAEL (mg/kg/day): M 

## = 25 F 

## = 2.5 LOA EL (mg/kg/day): M 

### = 125 F 

### = 25 M : Based on increased incidence of cli ni cal signs (i.e

. . crythema

. feet swelling. conjunctivitis and eye discharge). changes in c lini cal chemistry and hem atology parameters (i.e

. . increased alanine aminotransferase. alkaline phosphatase. mean corpuscular volume. white blood cells. neutrophil s. and platelet counts: and decreased blood cholesterol. ca l cium. albumen. haemo glob in. mean corpuscular haemoglobin conc..:ntrations and a l bumen / g lobulin ratio). increas ed adrenal wcigh1. and increased incidences of pe r iac in ar hcpatocytic degeneration. F: Based on decrea s ed blood g luco s e concentration

. At 125 mg/k g/ day (i.e

.. the dose

- level above the LO EL)

. th e fo ll ow in g effec ts were also observed: decreased body weight. blood glucose. and urea conccntra1ion: and increas..:d kidne y and liver wei!!hts.Table 4.2. Subcbronic , C hr on ic and Other Toxicity P r ofil es for Bromuconazole. 

### . , 

# . . Guide l ine S tud y T ype MR.ID (yea r ) I Doses I Resu lts C lassification


### . . 

### - 870

. 3200 21 /28

- Day 430 1 8504 (1993) Dermal Irritation Dermal Toxicity Dermal Dose (mg/k g/ day) : NOAE I

. (mg/kg/day): M = NA f s NA ( Rabbit ) M: 0. I 00. 500. I 000 LOAEL (mg/kg/day): M = NA F = 'A F: 0. 1 00.500. 1 000 Unacceptable I Guide lin e Svstemic NOAEL (mg/kg/day): M = NA F = NA No te : This study is classified as LOA EL (mg/kg/day) : M = NA 

## r- = NA unac ceptabl e because the applied test material did not co ver I0% of th e body 's swface area . U nd

e r the conditions of this study. th e dermal systemic toxic ity and dermal irritation NOA El -S cann ot be determined

. 43018504 ( 1993 ) Dermal Irritati on Dermal Dose (mg/kg/day): NOAEL (mg/k g/day): M = 10 00 f = 1000 M: 0. I00. 500. I 000 LOAEL (mg/kg/day): M > 100 0 F > 10 00 F: 0. I 00

. 500. IO OO Acceptab l e I Guideline Sy stemic NO AEL (mg/kg/day): M = 10 00 F = IOOO LOAEL (mafkg/day): M > 1000 F > IOOO 870

. 3465 90-Day NA Stud y requirement waived (T XR0057274 ) Inhalation Toxicit y 870.3700 Prenatal 42937 1 27 ( 1990) Maternal Developmental Main Study 1 OAEL ( m g/kg/day) 70 Toxicity Study Gavagc Dose (mg/k g/day): LOAEL ( m g/

k

g/day) = 500 ( Rat) F : 0. IO. 70. 500 Based on increas ed water con sumption during the do si ng period. decreased body wei g ht gain during 42937126 ( 1990 ) GD 6

- 10. and increased absolute and relative liver Range Pinding Stud y weights. Additionally. one dam wa s sac ri ficed after exhibiting neurotoxic cholincrg ic-type clinical signs Acceptable I Guideline th at had been previou s l y ob se rved in the range finding study Dcvclo12111cn tal NOAEL ( mg/k g/day) = 1 0 LOAEL ( mg/k g/day) = 70 Based on increased placental weight s and increased incidence of additional cervica l ribs. 430 18 508 ( 1991) Maternal Dermal Dose (mg/kg/day): NOAEL ( mg/k g/ day) = -1 0 F: 0. 40. 133. 400 LOAEL (mg/k g/day) = 133 Acceptable I Guidelin e Ba se d on clinical signs ( i.e

.. ungroomed and unkempt coat). Devclo12mental NOA EL ( mg/k g/ day) = 40 LOAEL ( m g/

k

g/day)= 13 3 Ba sed on increas ed fetal and lillcr incidence s of ske let al variations (i.e

.. one extra rib or a pair of extra rib s).



### Page 1 3of 18Tabl e4 .2. S ubc hroni c, C hr o ni c a nd O ther Toxi city Profil es for Bro mu con a zo le. G uid e lin e S tud y T y p e Prenatal Deve l op m ental Toxicity Study (Rabbit)

870.3800 Reprod uc tion and Fertility Effects ( Rat)

870.4 100 C hronic Toxicity ( Dog) MRfD (yea r ) I Doses I C la ss ificati on 42937129 ( 199 0) Main S tud y Gavage Do s e (mg/kg/day): F : 0. 12.S, SO, 200 42937128 ( 198 9) Range Finding Study Acec.:ptabk I Guideline

42937 1 30 ( 1989) 43029901 ( 199 0) Oiewry Concen tr ation (ppm): 0

. 20.200. 2000 Dietary Do se (mg/kg/day): M o : 0. 1.3. 13.8. 141.2 F

o: O. 1. 6. 15.S , I S9.6 Acceptable I Guideline

42937124 (199 1 ) Capsule Dose (mg/kg/day): M: 0. 2.5. 25. 125 F: 0. 2.S. 2S. 125 Acceptable I Guideline



### P ag e 1 4of18 Res ul ts Maternal NOAEL (mg/kg/day) = 1 2.5 LOAEL { mg/kg/day) = SO Based o n in creased clinical s i g ns (i.e

.. lethargy / relu c tanc e to move. increased re sp iration rate. ataxic/unsteady gait. aggression. lack of musck tone and coordination. prone posture. and vocali za tion ). decreased body weight gain. and decreased food consumption. Developmental NOAEL (mg/kg/day) = 50 LOAEL (mg/kg/day) = 200 Based on decreased live fetuses. increased post implantation loss. and increas ed re so rptions. Parental

OAEL (mg/kg/day): M = 13

. 8 F = I S.S LOA EL (mg / kg/day): M = 141.2 f 

## = I S9.6 Based on decreased body weight gain

. increased liver weigh ts. a nd increased incidence s of hepatocytic fatty vacuo lation. Reproductive I Off..,pring NOAEL (mg/kg/day): M = 1 3.8 F = 15.S LOAEL (mg/kg/day): M 

## = 141

. 2 F 

## = 159 .6 Oased on decreased pup viabi lity in the firs t generation and decreased pup body weight gain during lactation in both ge n erat i ons. NOAEL {mg/kg/day): M 

### = 25 F 

### = 2

. 5 LOAEL { mg/kg/day): M = 1 25 F = 25 M: B ased on swelling and aca nth os is/ hyperkcrat osis/ swl.!at gland hyperplasia and inflammation of the feet: increased incidence of reddened g um . adre na l co rti cal fatty cavuola tio n and zona fasciculata hypertrophy: increased white blood ce ll. l y mph ocyte. and platelet coun ts, alanine and aspartate amino -transfcrase activities. weights: decrea sed body we i ght. cholesterol. albumen/ globulin ratio. albumen

. and mean corpuscu lar haemoglobin concemration s a nd mean corpuscular haemoglobin. Incre ased incidence of rena l cytoplas mi c pigmen t in co ni c ul ar epithelium. pancreatic exocrine cell degeneration. urine volume and paler appea rance and decreased urine specific gravity. F: Based on increased inc id ence of adrena l cortical fatty vacuolation and decreased mean corpuscular haemo g lobin concentration and mean corpuscu l ar hcmoelobin

.Tab le 4 .2. S ub c bro n ic, C hr o nic and Oth er Tox ic i ty Pr ofil es fo r Bromu co n azo le. G ui de lin e Study T yp e MRJD (year) I D oses I Res ul ts C la ss ifi catio n NA 7 -W eek Oral 42937125 (1989) Non -Li ver Toxicitv Toxicity Range rind in g Stu dy NO/\EL ( m g/kg/day): M = 220 F = 3 1 9 (Mouse) Dietary Concentration (ppm): LOAE L (mg/kg/day): M = 637 F = 790 0.250.650. 16 00 .4 000. 10 000 Based on increased sp l ee n we ig ht in bo th sexes. Dietary Dose (mg/kg/day): decreased brain weight in males. and decreased heart M: 0. 35.2. 91.7. 220. 1. 637.0

. weight in females. 1 604.0 F: 0. 48.95. 123 .3

. 3 19 .0. 789.5. Liver Toxicitv 2036.0 NOAEL ( m g/kg/ day): M < 35 F < 49 Acceptab l e I Non

- Guideline LOAEL (mg/kg/day): M = 35 F = 49 Based o n inc r eased in cide nce of liv e r effec ts (i.e

.. hepatic in nanm1 ation. periacinar hepatocytic fatty vacuolati o n. and hepat ocvtic hypertrophy), 870.4200 Carcinoge nicit y 430 1 8506 ( 199 1) NOAE L ( mg/k g/ day): M = 57.4 F = 60

. 8 (Mouse) Dietar y Concentration (ppm): LOAEL ( mg/k g/ day) : M > 57.4 F > 60.8 0.20

. 1 00.500 Die tary Dose (mg/kg/day): M: 

## o. 2.27. 11.3. 57.4 

### r: 0. 2.40. 1 2

. 3. 60.8 U nacceptable I Guideline No te : This swdy is classified as unacceptable because the dose levels utili=ed were not adequate fo r assessing ca rci11 oge11ic JJO/ential. 430 185 07 ( 1 993) NO/\E L ( mg/k g/ day): M = 10.8 F = 1 2.3 Dietary Co n ce ntrati on (ppm): LOAEL (mg/k g/

day): M = 11 2.9 F = 1 34

. 5 0

. I 00

. IOOO

. 3000 Ba sed on decreased body wei g ht gains. Dietar y Dose (mg/kg/day): M : 0. 10.8. 11 2.9. 369.9 There is no increas ed risk of cancer in thi s s tudy. F: 0. 1 2.3. 134.5. 4 28. 7 Acceotable I Guidel i ne 870.4300 Combined Chronic 42937132 ( 1 992) OAEL (mg/kg/day): M = 0. 88 F = 1. 09 Toxicity I Die tary Co ncentration (ppm): LOAEL (mg/kg/day): M = 6.48 F = 8 .27 Carci no ge nicit y 0. 20. 150. I 000. 2000 Based on increased non-neoplastic liver le sio ns in ( Rat) Dietary Dose (mg/kg/day): females. 

### M

: 0. 0

. 88. 6
. 48. 43 .3

. 87

. 2 F: 0. 1. 09. 8 .2 7. 55 .6
. 114 .2 TI1ere is no increased ri s k of ca ncer in this s tud y. Acceotable I G uid el in e 870.5100 Bacterial Rever se 43018509 ( 1988 ) There was no evidence of induced revcrtant colonies Mutation Test Applied Dose ( μ g/platc): over bac k g round at an y dose tes ted. e ither with or (Salmonella ± S9: 50. 1 58. 500. 1580. 5000 without S9. typhimuri11m) Accep table I Guideline 42937 1 33 ( 1 989) Th ere was no evidence of induced rcvertant colonies Applied Do se**(~1glplate):** over background at any dose tested. ei ther with or ± S9: 5. 16. 

## so . 1 58. 500 without S9. Acceptable I Guideline



### Page 15of 18Tabl e 4 .2. Subchronic , Ch r o nic a nd Ot h er Toxicity Profiles for B r o mu co n azo le. Guideli n e S tud y T y p e MRlD (yea r ) I Do s es I R es ults C l a ss ifi ca t io n 870 .5300 in vil ro 42937 1 34 ( 1990) There was no unequi vocal evidence of induced Mammalian Ce ll Applied D ose (mg/ml. ): forward mu1a1ion a1 the HGPRT l ocus over so l, ·en t Gene Muta1ion -S9: IO. 1 5. 25

. 35. 50. 75. 1 00. control val ues. Tes! 125 (C hine se Hams1er + S9 : 25. 50. 1 00. 200. 250. 350. V79 Cells) 500 U

nacce ptable I Guideline .\'0 1 e: The nega/il'e findings i111he presence of S9 m ix miglu be accep1able 10 EPA 

### if 1h e inconsis 1 e111 res11/1s in cells exposed 1 0 DMBA i n the presence of S9 mix were clarified. Acceptable of !he 11 egG1ive r es ul1s in 1he absence of S9 mix would r eq uir e 11ega1ive r e rnlrs in GI leas! one addi1iona/ c1ssay in which ce lls were lrea 1 ed wilh 1111eq11ivocal/ y cy101oxic doses of

LS860263 as well as a dose of 2 5 Jlf

d mL. 870 .5 375 in vi1ro

-12937136 ( 199 0) In 1he absence of S9 mix. statis1ically significan1 Mammalian App lied Dose (μglmL): increases were see n in th e mean percem of Chromosome ±S 9 : 1 0,50, 10 0 .250 me1aphascs with ch romosomal aberra 1i ons at 1 0 and Aberration Test Acceptable I Guideline 50 μg/mL when gaps were excl ud ed from the (Chinese H amster de11.:m1in ation

. In the pre se nce of S9 mix. Ovary (C HO-KI ) sta ti s tica ll y signi ficant increas es were seen at I 0 and ce lls) 50 μ g! mL whether ga p s were included or excluded from the determination

. While there were increase s at I 00 μ g/ mL. both with and without S9 mix

. the increase s were not s tati s ticall y s ignificanL likely due t o reduc ed bioavai lab ilit y ofte s t material as mentioned with re spe ct to cytotoxicity. in vi1r o 42937135 (1989) No s tati s tically significant increases were seen in the Mammalian Applied Do s e (pp m): mean percent ofmetaphas es with chromosomal C hromo some -S9 : 6
. 25. 12

. 5. 25. 50 aberrations at any co nc e ntration of test materia l Aberration Test + S9: 25. 50. I 00. 1 25 evaluated. either with or with o ut S9 mix or" hen ( llum an Acceptable I Guidelim : gaps were included or excluded from the Lymphocyte s) determination

. 43521101 ( 1994 ) There was no evidence of a cl as to gc nic response in Applied Do s e (pp m): the absence of S9 activation. However. the S9

- -S9: 25. 5 0

. 100 activated test materi al induced do s e-related increas es + S9: 50. 100. 200. 225 in th e numbe r and percentage of cells with s tru ctura l Acceptable I Guideline aberra ti ons over a concentration range of 10 0 1 0 225 μ g/ml. The re s pon s e wa s s ig nificant (p <0

. 05) at 225 μg!ml. We c o nclude. therefore. that the s tudy provided acceptable evidence that S9

- act ivat ed bromuconazole wa s clas togenic in human l y mphocytes. 870

. 5395 Mammalian 42937137 ( 1990 ) LS860263 was tested to an adequate top do se and E !)1hrocyte Gavage Do se ( mg/kg): did no t signifi cant l y increase the frequency of Micro nuclcu s Te s t 40.200. 1000 mi cron uc l eatcd polychromati c erythrocytes in mou se (Mouse) l\cceptabk I Guideline bone marrow a t any do se o r sa mpling time te s ted

.



### Page 16of18Ta ble 4 . 2 . Subc h roni c, C hroni c and Oth er T ox icity Profiles f o r Bromu co nazol e. Guid e lin e S tud y Type MRID (year ) I Do s es I R es ul ts C lass ifi cation 870.SSSO Unscheduled DNA 43018SIO ( 1989) TI1ere was no evidence of UDS induction at any Synthesis in Applied Dose (μg/mL): te s ted concentratio n as meas ured by incorporation of Mammalian Cells Run I : 0.391. 1.24. 3.91. 12.4. 39. 1 tritiated thymidine into D A (us in g liquid in C ulture Run 2 : 0.39 1. 1.24. 3.91. 12

. 4

. 39. 1. scin tillation counting). (Rat Hepatocytes) 1 24 Acceotablc I Guideline 42937138 ( 1993) The mean net nuclear grain count was below zero for App lied Dose**(~1g/mL):** both dose s at both t reatment times indicatin g no 189 .7. 600 induction of UDS as tested in this s tudy. There was a Acceptable I Guideline 2

. S fold increase in the proponion of cells in S-phase in cu lt ure s from treated rats of both dosage g roups sac ri liced at 12-14 hours

. Only slides from the 12-14 hour time ooint were analyzed for S-ohasc synthe sis. 870.6200 Acute NA Study requirement wa i ved (TXROOS7274) eurotoxicity Screening Battery 90-Day NA Study requirement waived (TXROOS7274) Ncurotoxicity Screening Battery 870.748S Metabo l is m and 430 1 8S l I ( 1 992) Under the conditions ofthe s tudy [ si ngle ora l high Pharmacokinetics Gavage Dose {mg/kg): dose ( 1 SO mg/kg). single oral low dose ( 15 mg/kg). (Rat) Single : 15. ISO and repeat ( 14 day s ) oral low dose ( 1 5 m g/kg) t o 5-8 Repeated : IS (14 Days) Fi s her 344 rats/sex 

### I

. the mean recovery of radio label Acceptable I Guideline was - 9S% to I 02%. Pancrns of excretion of radiolabel were similar for all orally dosed groups. but there were significant difTercnces between the sex es. Females excreted hi gher levels [-43% to

- 46% vs. - 30% to

- 34%] of rad io label via the uri ne. while males excreted higher levels [

- 65% to

- 73% vs. - 51 % to

- 60% ] via th e feces

. ll1e majority of the radiolabel excreted via both uri ne and fece s occurred within the first 48 hours po s t do se. At all dose le vels. low levels of radiolabel [0 .04% at high dose: 0.02% at low do se (s i ngle and repeat) ) were detected in ti ss ues at 7 days post dose 

### Iboth sexes]. Bromuconazolc was well absorbed. extensively metabo l ized. a nd rapid l y eli min ated. Approximately 60 metabolites were detected. and S7 of these were assigned s tructure s. Major routes of metaboli s m involved extens i ve modification of the tctrahydrofuran rin g to give rise to LS 8020S0 [X24 j followed by variou s conjuga t ions. which resulted in the X4 series of metabo lite s. I lydroxy metabo lites of Bromuconazole were detected both free [X l 9A/B] and as sulphate ester conjugates. Although there was rapid and exte n sive metabo lism

. Bromucona z ole wa s found in the urine and fecal extract s . and conjugated Bromuconazole dia s tereoi so mers were found in the uri ne. 870.7600 Dermal Penetration NA NA 870.78 00 1 mmunotoxicit y NA Study requirement waived (TX ROOS6730)



### Page l 

### 7 of l 8

### Attac hm e nt 5 

### Toxicology Data Requir e ments The requirem e n ts (40 CFR 158.500) 

### for non -food use s are in the table below. Use of th e new gu id eline numbers does not imply that the new ( 1998) g uid e line proto co l s were u sed.
Tab le 5. Toxicoloe y Dat a Requirement s Guid e lin e S tudy T y pe Required S ubmi tted 870

. 11 00 Acute Ora l Toxic iw Ye s 870.1200 Acut e De rm al Tox i c it y Y es 870

. 1300 Acute Inh alation Toxicit y Ye s 87 0.2400 Acu te Eye Irritation Yes 870

. 2500 Acu te Dermal Irrit ati on Y es 870.2600 Skin Sensitization Yes 870

. 3 100 90 -D ay Ora l Tox icit y in Roden ts C R 870 .3 150 90

- Da y Oral Toxici t y in Non -Rodents CR 87 0.3200 2 1 / 28-Day Dermal Toxic it y No 870.3250 90

- D ay Derm a l Toxici ty Y es 870 .3465 90

- Day Inh alatio n Toxicity CR 8 70.3700 Pre nat a l Developmental Toxic it y Stud y (Rat) Yes Prenatal D evelopmental Toxicit y S t udy ( R abbit) Yes 870.3800 Reprod uction and Fe rtilit y EITec t s Ye s 87 0.4 100 C hr onic T ox i c it y ( Rode nt ) C R 87 0.4200 Ca rcinogenicity ( R at) CR C arcinogeni c ity (Mou se) C R 870.5100 Bacterial Re verse Mutation Test Yes 87 0.5300 in vitro Mamm a li an Ce ll Gene Mut atio n Test Yes 1 870

. 5375 i11 vitro Mamma li an C hromo so me Ab e rrati o n Test 8 70.5385 Mammalian Bone Marrow Chromoso m al Aberration Test Yc s 1 870

. 5395 Mammalian Ervt hr ocytc Micronucleu s T es t 870 .6 100 Delayed Neurotoxici ty of Organophosphoru s S u bstances (Ac ute
. 1 le n) C R De l ayed Neurotoxicity ofOrganophosphoru s Substances (28- Day. Hen) C R 870 .6200 Neurotoxicity Screening B a ttery (Ac ut e. Ra t) Ye s Neurotoxiciry Screenine B attery (90

- 0ay. Rat ) Yes 870 .6300 Deve l op mental Neuro tox i ci t y S tud y CR 870 .7200 Companion Animal Safety C R 87 0.74 85 Met abo li sm and Ph armacokinet ic s C R 870

. 7600 Derm a l Pen e tration C R 870 .7 800 lmmun otoxicity Yes C R Co ndit ionally R e quire d 1 A ot Applicable E ither g uid e lin e s tu dy ty p e ma y b e u s ed to sa ti sfy the dat a requirement (e.g

.. 870 .5300 or 870.5375) R

eq uireme nt waived ( TXR0056730. 1 3 Au gus t 201 3) Requirement waived (TX R0057274. 25 Jun e 20 15 )



### P age 18of18 Ye s Ye s Y

es Y1.: s Y

es Yes Ye s Yes Ye s No No Y es Yes Ye s Y

es Ye s Yes Yes Ye s Ye s No Ye s No No No No No No Ye s No No S ati s fi e d Yes Yes Yes Yes Y es Yes Ye s Ye s Ye s NA Ye s 3 Y es Y es Ye s Ye s Yes Y es Yes Ye s Yes NA NA Yes 3 Ye s 3 NA NA Ye s NA Yes 2