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

MEM O RAN D UM
D A TE: November 24, 20 I 5 OFFICE OF CHEMICAL SAFETY A ND POLL UTI ON PREVENTION



### SUBJECT: Metconazo le

. H uman Hea lth Sco pin g Document in Suppo rt of Re g i strati on Re view

.



### P C Co de : 125619 

### D ec i s ion No .: 505195 

### P etition No. : NA


### Ri s k Assess m e nt Type: NA 

### TXR No

. : NA 

### MRID No.: NA 

### DP Barcod e: D 428304 

### Re gi s tra tion No.: NA 

### R eg ulato ry Action: Registration Review Scoping Document 

### Ca s e No.: 7049 

### CAS No.: 1 251 1 6-23-6 40 

### CF R : I 80.617 

### FROM: Barry O ' Keefe , Sc

. ni o r B io. l ogis t 

# /3,**~<** . 

### Nancy Dodd, Chemist**~.** 

### Myron Ottley, Senior Biologist /U0Jp-l 

### Ri sk Assessment Branch Ill (RAB3) H ea lth E ffects Division (7509 P ) 

### THRO UG H : Christine Olinger , Branch Ch ief Ri sk Assessment Branch 

### rII (RAB Health Effects Division (7509P)


### TO: Jo rd an Page , Chemical Review Manager Jill Bloom , Team Leader Linda An-ington , Branch Chief Ri sk Management a nd Impl e m entat ion Branch 5 (RMIB5) Pe st icide Re-Evaluation Di v ision ( PRO ) (7508P)



### E x ec utiv e S umma ry Following is the H ea lth Effec ts Division 's ( HED's) human h eal th scoping docume nt for th e fungicide metconazole to s upport Regi s tration Review. To eva luat e th e scope of work n ecessa r y to s upport Registration Review , H ED has cons id ered previous risk assessments for metcon azo le ; updates to its toxicity, exposure , and u sage databases; an d the latest Agency science policy a nd ri s k assessment methodologies. The most recent H ED risk assess ment for metconazole was completed in 2014 ( D418 67 1 , B. O'Keefe , 12/15 / 2014).

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### The t ox icological database for metconazole is complete , except for a subc hr onic inhalati o n toxicity st ud y required in accordance with the 2007 40 CFR P a rt 158 toxicology data requirements. HED wi ll co nsider the ex istin g toxicit y database as well as any additional toxicit y s tudies received during registration review and w ill reevaluate points of departure (PO O s) and safety factors (SFs) used fo r ri sk assessment purposes. The li ve r is the primary target organ (with observed adve r se effects such as increa se d liver weight and e nzym e activity, increased incid e nce of hypertroph y and vacuolization) in the mouse. rat and dog. Other adverse effects observed inclu ded decreased body weig ht , blood effects (red uction s in erythrocyte and / or platelet parameters), splenic effects (inc luding increased spleen weig ht and hyperplasia) , lenticular degeneration (cataracts), and gastrointestinal irritation in the mouse , rat , dog and/or rabb it. Metconazo le is classified as "not likel y to be ca rcin ogenic to human s" at levels that do not cause mitogenesis. The FQPA Safety Factor has be en reduced to lX , since there are no res idual uncertainties for pre- and/or po st- natal toxicity.
The re s idue c hemi s tr y database for m etco na zo le i s adequate to s upport cuITent Re g istration Review data requirement s. Adequate metabolism s tudi es (crops, li ves t ock, and rotational crops) , storage stability , magnitude of the re s idue , and processing data are availab le to support the registered uses. Adequa te methods a re available for enforcement of th e currently established tolerances.
New dietary risk assessments are not anticipated during Regi s tration Review , unl ess there are changes to the drinking water ex posure estimates that n eed to be incorporated.
The residential and occupational exposure databases are adequate to s upport the R eg istration Review pro cess for metc o nazole. Re s idential and occupat ional handler and post-application exposure a ssessme nts are reflective of maximum app li cation rates and current exposure polici es and data, and did not id en tify ri sks of concern. However , · at the time of Re gistration Re view, HED wi ll reevaluate the points of departure and uncertainty factors currently used for ri sk assessment purposes regarding inhalati on expos ur es. Based upon that reevaluation , H ED will determine if updated reside nti al a nd occ up ational handl e r inh a lat ion ex posure risk assessments are needed.
HED w ill examine the n eed for a vo latilization assessment, as well as eva luate th e potential for exposure from spray drift during Regi s trati on Re view

. However, for metconazole , several enduse products are labeled for use on re s identi a l turf. Thu s, the ri s k assessment for res idential turf may be considered protective of any type of exposure that would be associated with sp ray drift. Resid en tial bystander exposures resulting from off-site transport (i.e., volati li zation) may occur as a result of occupational applications of metcon azole. The n eed for a bystander risk assessment for metcona zo le wi ll also be con s id ered during Re g i s tration R eview.
At the time of Re gis tration Review , HED will reevaluat e the points of departure and unc e rtaint y factors currently u sed for risk assessment purposes regarding inhalation exposures. Ba sed upon that reeva luation , HED will determine if updated aggregate exposure risk assessments are need ed.

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### Intr od uction
Metconazole i s a bro ad-s p ec trum triazole fungicide acti ve ingred i e nt that works sys te mi ca ll y by pre ve ntin g spo re formation and infobitin g myc e li al growth. Metconazole ac ts primar il y a s a n inhibitor of e rgosterol biosy nthe s i s, th ereby int e rf e rin g w ith synthesis of f un ga l cell membran es and providing systemic seed and seed lin g protection.
The most rece nt hum a n h ea lth risk assessment fo r met conazo le was completed in 20 I 4 for new uses on dry she ll ed pea and beans (excep t soybea n) crop s ub gro up 6C a nd s unflo we r crop s ub gro up 20B , crop group expansion to rapeseed s ubgroup 20A, crop group co nv e r s ions to fruit , stone , g ro u p 1 2 -12 and tree nut cro p group 14-12 ( 041 8671 , B. O ' Keefe , I 2/15 / 20 14 ). Metconazo le i s curren tl y registered for use on numerous ag ricultur a l crops , includin g barl ey , bushberries, corn, cott o n , dry s h e ll e d pea and beans , oats , peanut , rapeseed , r ye, soybea n s, s tone fru it s , sugar beets , sunflower , sugarcane , tree nut s, tr iti cale , tub e ro u s and co rm vegetables , a nd whea t. I t i s a l s o r eg i ste red for use as a seed treatment fo r barley, ca nola , co rn , cotto n , oats, suga r bee t s , tritical e a nd wheat seeds. Addit io n a ll y, it i s r egiste r ed for u se on turf and ornamenta l s in residential sett i ngs. H omeowners ma y apply m etco n azole to res idential turf and orna m e nt a l s. Metconazole end use prod uct s ar e formulated as th e following formulation ty pe s: e mul si fiable co n ce ntrate s, fl o wabl e co n ce ntrates, sol ubl e conc e ntrat es, water di s persibl e gran ul es, granu lars and ready-to-u s e so luti ons . M e tco n azo le is also formulated int o products wi th o th er fung icides. Applications can be made w ith grou nd , ae rial , airb las t , c hemigati o n , hand h e ld , or seed treatment e quipm e nt. R e fer to Attac hm e nt I (Tab le I ) fo r th e chemical id e ntity of m e tcona zo le.


### H aza rd ld e ntifi ca tion ff oxicology
The toxicologica l database for metcona z o le i s com pl ete , excep t for a subchronic inh a lation stu d y which is required in accorda n ce w ith the revised tox ico logy data requirements ( TXR00570 53, 

### J. Les h in , 10/ 09/ 20 I 4 )

. The toxicit y datab ase a l so does n ot includ e a n acute neurotoxicity s tudy , but a waiver has been gra nt ed fo r the requirement of this stu d y (TX R0 056405 , K. Rury, 08 / 09/ 20 I 2).
Metco n azo le is a member of the triazole c lass of sys temi c fungic ides w hi ch acts primarily as a n inhibitor of ergos tero l biosynthesis. Th e propo sed mode of ac tion for m etco n azo l e i s via inh i bit ion of s tero l (ergos tero l) biosynth es i s in fung i wh ic h i s con s i s te nt w it h altere d c h o leste rol level s observed in mi ce a nd rats.
Overall , m e tc o na zo le appears t o a ffect th e li ver, kidne y, s p le en , and var ious blood paramete rs in all the s pecies tested. Dose levels a t wh ic h these effects occ ur are s imi lar ac ross s p ec ies. Like other tri azo le s , a prim ary target o rga n in m a mm a lian to x ic ity studies i s th e li ve r . Li ve r toxic i ty was see n in the mous e , rat and do g fo ll owing o ra l expos u re to m e tconazole via subc hron ic o r chronic exposure durations. Wh il e li ver effec t s have been repo rt ed consis tent ly across multipl e exposure durations and spec i es , these effects we r e considered s li g ht or minimal i n so me stu dies a nd appeared t o be adaptive respo n ses. Howev e r , based o n the weight of ev id e n ce from th e consi s tency of these reported effects and evidence that these effects in crease in seve rit y w ith exposure durat i o n , l ead in g to li ve r tumors in th e chronic mouse s tud y, th ey were co n si d e r ed a d ve rse a nd fo rmed th e bas i s of th e study LOAEL s. M e tco n azole indu ced liver tumors in mal e

Pa ge 3of2 7

### and female CD

- I mice. 

### It i s classified as "Not likely to be carcinogenic to humans " based on acceptable mode of action studies which establ i shed a mitogenic mode of ac tion for the li ver tumors. There is no concern for mutagenicity/ ge n otoxicity. The chronic RID would be protective of liver tumor induction via mito genes i s. Oth er maj or critical effects observed in oral studies were decreased body weight and blood effects (reduc ti ons in erythrocyte and/or platelet parameters) in the mouse, rat, dog and / or rabbit. Sp leni c effects including increased spleen we ight and hyperplasia were observed in th e mou se , rat and do g at dose lev e l s where liv er effects were a lso observed

. In dogs, lenticular degeneration (cataracts) was observed at the highest dose tested (114 mg/kg/day). Furthermore, at high dietary levels , there is ev idence that metconazole is a gastrointestinal irritant in the do g. Metconazole was not immunotoxic or neurotoxic in the appropriate studies conducted.
There was no quantitativ e susceptibility to the fetuses of rabbit s following 

### in utero exposu re to metconazole. In the prenatal developmental toxicity study in rabbits , developmental effects ( incre ase d post-implantation lo ss and reduced fetal body weights) were observed at the same dose th at caused maternal toxicity (reduced food consumption and alterations in h e matol ogy parameters). ln the two-generation reproduction study in rats, offsprin g toxicity (reduced fetal body weights F2 offspr in g and decreased viability in F l and F2 offspring) was observed only at the highest tested dose, a dose which also resulted in parental toxicity as evidenced by reduced parental body weight , increas ed incidence of fatty hepatocyte changes in mal e parental animals a nd increased incidence of spleen congestion in FI parental females. ln the developmental toxicity study in rats, an increased incidenc e of p ost-i mplantation lo ss, hydroceph aly and v isc eral anomalies (cranial hemorrhage , dilated renal pelvis , dilated ureters , and displaced testis) were report ed, in the pre se nce of material t ox icity. Skeletal variations (predominantly lumbar ribs) occurred in the absence of maternal toxicity. Ho weve r , ther e is lov.r concern for quantitative suscept ibility (skeletal variati on in the absence of maternal toxicity) because the endpoin t and point of departure for risk assessment are based on the effects in the fetus, for which there is a clear no-observed effect level (NOAEL)

. Therefore, it is concluded that there is no residual uncer taint y for pre- and/or po s t-natal toxicit y. The FQPA Safety Factor ha s been reduced to IX.
Acute ora l and dermal toxiciti es are Category Ill , while ac ute inhalati on i s Categ ory IV. Metconazole is a moderate eye irrit a n t (Category lll ) and a mild skin irritant (Category fV ). 

### rt is not a skin sensitizer.
Plea se ref e r to Attachment 3 for a summary of the toxicity endpoints and points of departure (PODs) for metconazole , and to Attachment 4 for th e complete toxicity profile tabl es for metconazole.
Conclusions: The toxicology database for metconazole is not complete for risk assessment of the current use s , in th at a subchronic inhalation toxicity study is required and rema in s a data gap. As a result , a database uncertainty factor (UFo a ) of 1 

### OX h as been appl ied to the risk assessments of inhalation exposures. At the tim e of Registration Review , or when the required subchron ic inhalation toxic ity study is submitted , HED will reevaluate the points of departure and unc ertai nty factors cmTently used for risk assessment purposes regarding inhalation exposures.

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### R es idu e C h e mi s try a nd Di e tary Ex p os ur e 

### The na ture of the r esidue in pr imary/ rotationa l crops and lives tock has be e n adequ ate ly d e fined

. Metconazole (pa re nt ) is the residue of co ncern for the tolerance expressio n for primary/rotational crops and live s tock. Metconazole is the residue of concern for ri sk assessment purpo ses in prim a ry and rotational c rops , except fo r cereal g rains; th e residue s of conc e rn for ri sk ass ess ment in cerea l grain s (as both primary an d ro tatio nal cro ps ) are metcona zo le and the metabol ite M 11. The residues of co ncern in li vestock fo r purposes o f th e ri s k assessment are metc o nazole and metab o lites M I ( free/ unconjugat e d a nd its gl ucuronic ac id co n ju gate) , M 12 , and M3 l 

### (free and its gl ucuro ni c ac id conjugate). Fo r drinkin g wa t e r, the res idu e of co nc e rn fo r met co nazol e is th e parent o nl y . HE D also has concern for r es idue s of 1 ,2,4- triazo le, 1riazol y l a lanin e (TA) and tr iazolylacetic acid (TAA) in pl a n ts and I

### ivestock as a re s u lt of the use of me t cona zo le. Howeve r , because endpo int s for the se separa t e co mp o und s ha ve been established, ex po s ur e and risks fro m free tri azo le a nd it s co nju gates w ill be ad dresse d separately. The exis tin g re s idue chemistry database for me tconazo le is adequate to sup port current Registration Rev iew d ata require ment s. Adequ ate met abo li s m , enforcement meth ods , multircs idue method s, s torage s tab ili ty , field tri a ls, proc ess ing and rotational crop data ar e available to support th e reg i s tered us es. Analytica l refe rence s tandar ds for metconazole are curre ntly available in the EPA Nati onal Pesticide Standards Reposi tory (e -mail fro m The resa Cole, ACB , 7/ 31/15).
Ac ut e and chronic agg reg ate di e t a ry (food and drinking water) ex pos ure and risk assessments were conduc t ed in 2014.
The acute and chronic assessments were conservative, us ing to l erance- level residu es except for cereal g rains and li vestock commodities , DE EM d efa ult o r e mpiri ca l processing fac to rs, a nd I 

### 00% cro p tre a ted. Since cereal gra in s and li ves tock commodities include metabolite s as res idu es of concern in th e ri sk assessmen t , maximum res idue valu es for th e metabolites from fie ld tri a ls we re added to the m c tco nazo le to leran ce le ve ls. Th e esti mat ed drinking water conce ntr ati o n (E DWC ) of 51.8 ug/L ( ppb ) used in the acute assessment was generated by th e 

### PRZM-Ground Water ( PRZ M-GW) mode l. Th e EDWC u se d in th e chron ic d ie t ary assessment of 43.9 ug/L (ppb) was ge nerat e d by th e S urfa ce Water Co ncentrati o n Calcu lato r (SWCC) model.
T he acute dietary (food and drinking wa t e r) ex pos ure to metco n azo le is below H ED 's leve l of conce rn for fe ma les 1 3

- 49 yea r s ol d , the o nly population s ubgroup of concern. For the genera l U .S

. population , inc luding infant s and children , an appropriate dose/e ndpo i nt attr ibutable to a sing le dose was not observed in th e available oral toxi ci ty st udie s. The acute die tary exposure es tim ate at th e 95th perce ntile is 4.6% of the acute population adjusted do se (aPAD) for females 1 3 -49 years o ld , th e only popul a tion subgroup of co ncern. The chron ic dietary (food and drinking water) e xposure to metcona zo le is below HE D 's leve l of co nce rn for th e ge ner a l U.S. population and a ll 

### popu lation s ubgroups. Th e chronic di etar y

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### exposure estimates are 6.6% of the chro ni c popu latio n adjusted dose ( cPAO) for the general U.S. population and 14% of th e cPAO for c hildren l-2 years old , the most highly exposed population subgroup.
Metconazole was classified as " not li kely to be carcinogenic to humans;" therefore , a cancer dietary assessment was n ot performed. 

### Conclusions : A new dietary exposure assessmen t is not anticipated to be needed during Registration Review un less there are incre ases to the drinking water ex posure est imates that need to be incorporated.
Re s identia l Ex po s ure There are exist in g uses of metconazole on turf and ornamenta l s in residential settings that were reassessed in the most recent H E D ri sk assessment (0418671 , B. O ' Keefe , 12/ 15 / 2014) to reflect H ED 's 2012 Residential SO P s 1 

### along with policy changes for body weigh t assump ti ons. Because dermal toxicity endpoints for the approp ri ate duration of exposure ( s hort-term ) were n o t identified up to the limit dose , on ly r esidentia l handler inh a lation exposu re s / risks fo r adults , and residential post-application incidental oral exposures/ risks for children were asses s ed. For residential hand ler exposures to adu lt s , all inhalati on ri s k est im a tes were g reate r than the level of concern (LOC) of 1 , 000 , and therefore are not of concern ( MOEs ran g e from 6 , 300 to 23 , 000 , 000). For post-application exposures to sma ll chi ldren ( l to < 2 years o ld ) , all incidental oral ri s k estimates are greate r than th e LOC of 100 , and therefore are not of concern (MOEs range from 1 , 000 to 450 , 000).
In accordance with 40CFR§158 , turf transferrablc residue (TTR) data are required 

### for all occupational (e.g. , s od farms, golf courses , parks, and recreationa l areas) or residential turf u se s that could result in post-application exposure to turf. In the ab s ence of c h emical-specific TTR data , E PA uses default values. As mentioned above , an assess m en t of incidental ora l expos ures to small children , using th ese default va lu es , was completed as part of the most recent 

### H E D ri s k assessme nt (04 18 67 1 , 

### B. O'Keefe, 1 2115 /20 14). Since th e est imated residential turf postapplication e xpo s ure for residential turf using default TTR values for metconazol e is minimal in compa ri son to the leve l of concern (i.e. , the calcu lated MOE is greater than 10 time s higher than the level of concern , MOE= 

### I , 000 compared to the LOC of 100) , EPA has waived the 40 CFR TTR data r equirement. In thi s instance , it i s unlikely that chemical-specific TTR data w o uld b e needed to further refine exposure asse s sments. 

### I n accordance with 40 CFR 

### §I 58 , dis lodgeab le foliar residue (Of- R ) data a re req uired 

### for a ll o ccupati onal ( e.g. , crop , nurser y, greenhou se use s ites ) or resid e ntial (e .g. , o rnamental and vege tab le ga r dens , p ick yo ur own farms, retai l tree farm s ) use s that could r es ult in postapplication exposure to foliage. S in ce metconazol e doe s n ot re s ult in adver se syst e mic toxicit y via the dermal rou te of expos ure , EPA h as wa iv ed the 40 CFR OFR data requirement at this time.

1 Available: htt p : 

### I / www 2

. ep a. gov/ pesticide

- scie n ce - a nd -as s es s ing-p e st ici de

- r i sks/ sta n da rd -operati n g - pr oc ed u res - r e side n t i al- p esticide


### Page 6of27

### Sprav Dri ft and Volat ili za tion: Residentia l by s tander exposu res resulting from off-site transport (e.g

. , s pray drift o r volatilization) m ay occ ur as a result of app licati o n s ofmetcona zo le

. The potent ial fo r spray drift w ill b e quanti ta tivel y eva lu ated for eac h pe s ti c id e dur in g the Re g i s trati on R eview process th a t e n s ur es tha t a ll u ses fo r th at pe s ti c id e w ill be co n sidered concmTentl y. H owever, fo r metco na zo le , severa l e nd-u se products a re lab e le d for u se on r es id en tia l turf. Thus , the ri sk assessment for that u se may be co n sidere d protectiv e of an y ty pe of exposure that would be associa ted w ith sp ra y drift. Jn te rm s of vo la tili za ti o n , th e agenc y has de ve lo p ed a Volati li za tion Sc r ee nin g Too l and a subsequent Volatil izat io n Sc ree ning Ana lysis (h ttp: // www .regul a tion s.gov /# !docketDetai l : D = E PA-HQ -OPP- 2014-0219). Durin g R eg i s tration R eview, th e agency will utili ze thi s analysis t o determine if data (i.e. , flux s tudie s, route-specific inh a lat ion toxico log ical s tudie s) o r further analy s es are req uir e d for spec ifi c c hemi ca ls. 

### Concl us ions: Short-term residential expos ures are expected from ex i s ting u ses on turf and orna mental s. S ince th ese expos ur es ha ve been recentl y reas sesse d t o reflec t HED 's 2012 R es idential SOPs 2 

### a lon g w ith p o li cy changes for bod y weig ht ass umption s, HED does not ant ic ipate th e ne e d to rea sse ss th es e expos ures durin g Reg i stra tion Review. How ever, at th e tim e of R eg i stra ti o n Rev ie w, HED will reeva luate th e point s of departure a nd un ce rtaint y factor s cu rre ntl y u se d fo r ri s k a ssess m e nt purp oses r ega rdin g inh ala tion exposures. Based upon that reevaluation, I-I E D wi ll d e termin e i f updated res id ential handl e r inh a la tion ex po s ur e risk assess m e nt s are n ee ded.
The Agency w ill exa min e the n ee d for a vo la tili za tion asse ss m e nt , as well as evaluate the p o te nti a l fo r exposu re from spray drift dur i ng R eg i s tration R ev iew

. Howeve r , for metcona z ole , severa l end-use products a re lab e led fo r use o n residential turf. Thu s, the ri s k assessment for re s idential turf m ay be cons id ered protec ti ve of a n y ty pe of expos ure that wo uld be assoc i ated wit h s pra y drift. R es id en tial by s ta nd er expos ures res ulting from off- s ite t ra n s port (i

. e., vola tili za ti on) ma y occ ur as a res ult of occ up a ti o n al a pplicati o n s of m etcon azo le. The n eed for a bystander ri s k assess m e nt fo r m e tconazo l e w ill also be cons idered during R e gistration R ev ie w. 

### Ag g r egate Risk Assessment
In acco rd a nce wi th th e rood Qu a lity Protection Act (FQ PA) , HED must conside r and aggregate pesticide ex posure s and ri s ks from three maj or s ource s : food , drinking wat e r , a nd res id e nti a l ex p os ur es. The acu te and chron ic aggreg ate ri s k asse ss ment s includ e d food an d drinking water. The s hort-t erm a gg regat e risk assessmen t included food, drinking ware r , and re s id e nti al expos ures. No inte rm e di a te-term aggre ga te ri s k asses s ment was conducted s ince a ll re s id e ntial expos ure s a re antic ip ated t o b e s h o rt-t e nn in durat ion.
Acu te and C hroni c: Th e 20 14 acu te and chronic aggr eg ate ri s k assessme nt s includ e d ex p osu re to metconazole r es idues in foo d and drinking water. Acu te and c hroni c d ietary ri sk es tim a tes fo r food a nd drinking wate r ex po s ure a re b e low H E D ' s l eve l of co ncern (< 100 % of the a PAD and c P AD)

.

2 Av a il a bl e: http : / /www2

. epa . gov/pest.icide-science

- and-assessing-pesticiderisks/standard-operating-procedures-residential-pesticide



### P age 7of27

### Short-term: In 2014, a short -term aggregate risk assessment was completed for metconazole. For adults , the short-term aggregate assessment combined the average food and drinking water exposures with handler inhalation exposures on treated turf. For small children 

### (1 to 

### <2 years old) , the short-term aggregate assessment combined the average food and drinking water exposures with post-application incidental oral (hand -t o -m outh) exposures from contact with treated turf. The assessments resulted in risk estimates that are below the I-IED's level of concern (MOE < 100 for children , aggregate risk index (ARI) <1 ). The short-term aggregate MOE for c hildren was 

### 630 and the ARI for adults was 

### 5.3.


### Conclusions: Aggregate exposure to metconazole is current l y not of concern to HED. 

### A new aggregate assessment is not anticipated to be needed during Registration Review. However , a t the time of Registration Review , H ED will reevaluate the points of departure and uncertainty factors currently used for ri sk assessme nt purposes regarding inhalation exposures. Based upon that reevaluation , H ED will determine if updated residential handler inhalati on exposure risk assess m ents are ne eded; and thus , whether an updated agg regate assessment i s needed. 

### Occupational Ex po s ure A ll occupational exposure sce n a ri os for all current ly registered uses were previously assessed in several risk assessments (see References). Occupational handlers and post-application workers can become exposed to metconazole at short

- or intermediate-term durations ttu-ough its use. Because dermal toxicity endpoints for the appropriate durations of exposure (short- and inte rm ed iate-term) were not identified up to the limit dose, on l y occupational handler inhalation exposures/ risks were assessed. Occupational Handlers Previous occupational handler exposure and risk assessments for metconazole we re conduc ted at the maximum application rates and assumed the maximum area treated per day for all the registered use s it es . Applications can be made with ground , aerial, airblast, chemigation , hand held , or seed treatment equipment. Occupational exposure assessments have been updated in accordance with current HED policies and standard operating procedures. Risk estimates for all scenarios are not of concern with labeled personal protective equipment (P P E) , and therefore , HED does not antic ipate th e need to reassess these exposures during Registration Review. However , at the tim e of Registration Review , HED will reevaluate the points of departure and un certa inty factors currently u sed for risk assessment purposes regarding inh alation exposures. Based upon that reevaluation H ED will determine if updated occupational handler inhalation exposure risk assessments are n ee d ed. Occupational Post-Application Since metconazole does not result in adverse systemic tox icity via the dermal route of exposure , a quantitative derma l assessment is n ot req uired for metconazole or needed during Registration Review. Based on the Agency's curre nt practices , a quantitative occupational post-application inhalation expos ur e assessment was not performed 

### fo r metconazole at this time. 

### If new policies or procedures are put int o place , the Agency may revisit the need for a quantitative occupational post-app li cation inha lation exposure assessment for metconazole.

Page 8of27

### In accordance with 40Cf' R § 158 , TI R data are re quired for a ll occ up a tional (e

. g., so d farms, go lf cou r ses , park s, and rec reati o nal areas) or r esi d e ntial tu r f u ses that co u ld r es ult in postap pli cation exposure to turf. Additiona ll y, in accordance with 40CFR § 158 , DFR data are required for a ll occ upati ona l (e.g., crop , nurse ry, g ree nhou s e u se s ites) o r re s identi a l (e.g., ornamen ta l and vege table ga rden s . pi ck yo ur own fa nn s, re ta il tree farm s) u ses that co ul d result in po s t- a pplication e xposure to fo liage. However, as mentioned above, m etco nazol e doe s not resu lt in adverse sys temic toxicit y v ia the dermal route of ex p osure, a nd ther efo re. E PA h as wa ived the 40 CF R TT R a nd D F R dat a requirement s at thi s tim e . 

### Concl u s ions: The occ upational ex po s ure database i s adequate to s upp ort the R eg i s tration Rev iew proc ess for metconazo le. The occupational handl er and post-application ex po sure assess m e nt s are re fl ec ti ve of current exposure poli c ies a nd dat a, and th e refore, there is suffic ient information ava ilabl e to a sse ss occ upational handl e r and post-application expos ur es. Updated occ upationa l handl e r and post-applicatio n exposure assessments are n o t anti c ipate d t o b e need ed duri n g Regi s tration Revi ew. H oweve r , at th e tim e of Re g i strat ion R ev iew , H"ED will reevaluate th e p o int s of d e parture and unc e rtaint y factors curre ntly u s ed for risk assessme nt purpose s regarding inhalation e xpo s ures. Based upon that reevalu a tion, H E D will determine if updated occ upational handl e r inh a la tion ex po s ur e ri s k assessments are n ee ded

. P ubli c H ea l th a nd Pes t icide E pid e mi o l ogy Data


### In the Main OPP In ci dent Data Syste m (IDS) , from January I , 20 I 0 t o May 27, 2015 , th e re were no in c id e nt s reported for the single chemical metc o nazole on ly in th e d a taba se. Th e re were three in c ident s report e d involving metconazo le and p yrac lostrobin

. These incident s were classified a s moderate seve rit y.
In the Agg r egate ID S , from January I , 2010 t o Ma y 27, 20 15 , th e re were 1 7 in ci d ents rep o rted involving m e tco nazo le. These incidents were c la ss ifi ed as minor seve rit y. Overall , th ere a re few incident s reported to IDS involving m e tconazo le.
I\ 

### query of th e Cente r s fo r Di sease Contro l and Preve ntion/Nati o n a l In s titute for O cc upati ona l Safety a nd H ea lth (C D C/N TOSH ) Sent in e l Eve nt No tific a tion System fo r Occupational Ri sk

Pes ticid es (SENSOR)- Pe s ticide s database fo r 1 998-2011 id e ntifie s no cases involving metconazole

. T he Agricu ltural He a lth Study (A H S) i s a hi g h qu a lity, pro s pective epidemiology s tudy eva lu a ting th e lin k between pe st icide u s e and va riou s health outcome s, including cancer. The A H S include s private and co mm ercia l pes ti cide applicators and their s pouse s . Metconazo le -i s not included in the A HS, a nd th e refore , this s tud y d oes n ot provide informati o n fo r thi s report. 

### Concl us ion: Based o n the lo w fre quen cy and seve rit y of in ciden t cases reported for metconazolc in both IDS and SENSOR-Pesticides , there d oes not appea r to be a concern at thi s time that wo uld warrant further in ves ti gation. The Age n cy will co ntinu e t o monitor th e incident information and, if a conce rn i s trigger e d , additional analysis wi ll be in c luded in the risk assessme nt.

P age 9 of27

### To l e r a n ce Assess m e nt a nd Inte rn a ti o n a l Ha rm o n iza ti o n Tolerances are es tabli shed for plant and livestock commodities under 40 CFR 

### § l 80.6 l 7(a) for residues of metconaz ole , inc l uding its metabolites and degradates. Compliance wi th the tolerance levels is to be determined by me asu rin g only metconazole [5-[(4- chlorophenyl)methyl]-2 , 2-dimet h yl -1- (lH-1 , 2 ,4-triazol-l-ylmethyl)cyclopentanol) as th e sum of it s 

## ci s - and 

## trans

- isomers. No to lerances are established for Section 18 s , regional registration s, or indirect/inadvertent residues.
As shown in Attaclunent 6 , there are no Codex maximum residue limits (MRLs) estab li shed fo r m etco na zo le ; therefore, th e re i s no h a rmoni zat ion issue with Codex at this time. Residue definitions are harmon ized with Canada (D4 18671 , B

. O'Keefe , 1 2 / 15 /20 14 ). For commod iti es with both U.S. and Canadian tolerances /MRLs , most of the t o leranc e/MRL levels are the same. 

### C umul a ti ve Metconazole i s a m e mber of th e triazo le-containing class of pesticides. Although conazoles act simila rl y in plants (fong i) by inhibiting ergosterol biosynthesis, there i s not necessarily a rel at ion s hip between their pesticidal activity and their mechanism of toxicity in mammals. Structural s imil ari ti es do not constitute a common mechanism of toxicity. Ev iden ce is needed to estab l ish that the chemicals operate by th e sa m e , or essentially th e sa m e , sequence of major biochemical events. In co naz oles , h owever, a variabl e pattern of toxicological responses is found; some are hepatotoxic and hep atoca rcino ge nic in mic e. Some induce th yro id tum ors in rats. Some induce developmental , reproductive, and neurological effec t s in roden t s. Furthennore, the conazoles produce a div erse range of biochemical events including altered cholesterol levels , stress responses, a nd altered DNA methylation. 

### It is not clearly understood whether thes e biochemica l events are directly connected to th e ir toxicologic a l outcomes. Thus, there is current l y no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not fo ll ow ing a cumulativ e ri s k approach based o n a common m ec hani s m of toxicity for the conazoles. For information regardi n g EPA ' s procedures for cumulating effects from substances found to have a common mechanism of toxicit y, see E PA's webs ite at http: // www2.epa.go v / pesticide- s cience-and-asse s si n g-pesticide -ri s ks / cumulative

- a s sessme ntrisk-pesticides


### Human St udi es The risk assess ment s wh ich have be e n previous ly conducted for metcona zo le reli ed in pa11 on data from studies in which adul t human subjects were intenti onally exposed to a pesticide to det e rmin e th e ir dermal and inh a lation exposure. Many s uch s tudi es, in volv in g exposure to m a n y different pesticides , co mpri se generic pesticide exposu re databases suc h as the P est ic id e Handlers Exposure Datab ase (PHED), th e Agricultural Handler Exposure Task Fo rce (A H ETF) database , the Outdoor R eside nti a l Exposure Task Force ( ORETF ) , and th e Agricultural Reentry Ta sk Fo rce (ARTF) Database. EPA has r ev iew e d a ll the studies s upporting th ese multi-pesticide gene ric exposure d a t abases , and has found n o c lear a nd convincing evidence that the conduct of any of th e m was either fundam e nta ll y un ethical or significantly deficient re lativ e to the et hi ca l standards prevailing at the time the research was co ndu cted. All app li cable requirements of

Page 10 of27

### EPA's Rule for the Protec tion of Hum an Subjects of R esearc h (40 CFR P art 

## 26) have been sati s fied , a nd th e re is n o r eg ulatory barrier to continu ed reli ance o n th ese s tudies.


### D ata D e ficienci es The following toxicolo gy data are need e d to s upport the re g i s tered u ses of metcon az ole:
870 .3 465 Subch ro nic Inh a lati o n Study
A s ubchronic inhalation s tudy i s req uir ed because the u se of an oral point of departure (PO D ) for inhal a ti o n exposure res ult s in MO Es as low as 380 for o ccupational exposure , w hich does not m eet th e targe t of 

### I 000 for a wa iver (TX R0 0570 53 , 

### J. Lesh in, I 

### 01 09 1 20 14 )

. T h e refore , a l OX database unc e rtainty factor has be e n added for inhalation expos ures in the abse nc e of the requir ed inhal a tion toxicity st udy.


### Reference s
Recent Memoranda Rel eva nt to Rel!i stration Revi ew of Mctconazo lc

Author DPffXR # D a te Title Human He a lth Risk Assessments B

. O' Ke efe D308794 07 1 06 1 06 Metconazole: Hum an Health Risk Assessme nt for Pr oposed Tolerance on Imp o rt ed Bananas. B. O' Kee fc D32 8676 09 1 06 1 07 Metcona zo l e: Hum an Health Ri sk A ssess m en t for Propo se d New Uses o n Turf and Ornamentals. Yan 0 33 1926 03 / 12/ 08 Mctconazole: FQPA Hum an Health Ri sk Assessment for Proposed New Donovan Uses o n S ma ll Grain s, Ston e Fruits , Tree Nut s, Peanut s, Soybeans, and Sugar Beet s. B

. O ' Keefe 0 341748 08 1 1 5 1

08 Metconazole. F Q P A Hum an Health Ri sk A s sess m e nt fo r Pr oposed New Sectio n 3 Uses on Corn and Cotto n a nd Secti o n 18 Use on Su garca ne. B. O ' Ke efe D350369 10 / 20/ 08 Mctco n azole. Hum a n H ea lth Ri sk A s sess men t for Proposed Sec ti on 3 Us e on Canola. B

. O' K eefe D 362044 02/ 19 / 09 Metconazole: Add endum to th e Hum an Health Risk Assessmen t ( DP # s34 l 748 & 351382) for Proposed New Section 3 Uses o n Corn an d Co tton and Sec ti o n 18 Use o n Sugarcane. B

. O ' Ke efc 0375762 02 / 2 8 / 11 Metcona zo le. Hum an H ealth Risk A ssess m e nt for Seed Treatment U se on B a rle y , Ca nol a , Co tton , Oa t s, Triti ca le , Wheat, Com ( Fi eld , Swee t , and Popcorn), and S ugar B eets. B. O' K eefe D380512 05/ 24 / 11 M e tcona zo l e: Hum a n H ealt h Risk A sses sm e nt for Proposed Uses on Tuberous a nd Corm Veg etab les Sub grou p I C an d Bu shberry Subgroup 13-07 8

. B. O ' K eefe 0386421 09/ 30 / 11 Metconazole: Human He a lth Ri sk A ssess ment for P roposed Uses on S ugarcan e. J

. Dawson 0399532 08 /09/ 12 Metconazole. Summary of Ri sk I ssues Associated With In crease In Tolera nce For Corn S tov er . B

. O'Keef e 0418671 12 / 15/ 14 Metco nazo le - Hum an Hea lth Ri sk Assess ment fo r a Sec tion 3 R

egis trati o n ofNew Uses on Dry Shelled Pe a a nd B ea ns (Excep t Soybean) C rop Subgro up 6C and Su nO ower C rop S ub gro up 20 8 ; Crop Group E xpa n s ion to Rape see d Subgroup 20A; and Crop Group Conversions to Fruit , Stone, G ro up 12 -12 ; and Nut , Tree, Group 14-12. Res idu e Chemistry N

. Dodd 0309499 11 / 23 / 04 M e tc o nazo le R es idu e Chemistry D atabase Sco p e.



### Page 11 of 27R ece n t Mem o r a n da Re l eva n t to Re1rist r a ti on R ev ie w o f M etco n azo le Auth o r DP /TXR # D ate Titl e N. Dodd D3 2454 1 12 / 1

4 /05 Metconazole. R eq uest for a Tolerance on Imp orted Bananas. Summary of Anal y tical C he mi s try and Residue Data. Petition Numb er 9E05052. N. Dodd D348168 02 /20/08 Metcona zo le. Petition for Establishment of Tolerance s for U se o n Sma ll Grains , S tone l'ruits, Tree Nuts , Peanu ts, Soybeans, and Sugar Beet s. S ummary o f Ana lytic a l C hemi s try and Re s idu e Data. N. Dodd D34 I 746 05/ 0 1/ 08 Metconazole. Petition for Establishment of Tolerance s fo r Use on Corn and Co tton. S umm ary of Analytical C hemi s tr y and Residue Data. N. Dodd D350367 09/ 18/08 Metconazole. Petition for th e Es ta bli s hm e nt of a Tolerance fo r Use o n Ca nola. Summary of Analytical Chemistry and Re s idue Data

. D

. D36 1 I1 0 02 /26/ 1 0 Metcona zo le. R es pon se to Data Gaps fo r Conditional R eg i s t ra ti o n on Soderberg Small Grains , Stone Fruit s, Tree Nuts , Pea nut s, Soybeans , and Sugar Beets

. Sum mary of Analyti ca l Chemistry and Residue Data

. A. Aci e rto D371571 08 /20110 M e tc o n azo le. R espo nse t o Dat a Gaps for Condition a l Re g i s trati o n in/ o n Ca nola. Summary of Analytical Chemistry and Residu e Data

. D. Drew D363016 0 1 / 12112 Storage S t abilit y of 1,2 ,4-Triazole. Tri azo l y la l a nin e and Tri azo ly lace ti c Ac id in Var ious Crop Matrices and Processed Co mm odi tie s (up to four yea rs und er fro ze n storage). N. Dodd 0399057 07119/12 Metconazole

. Add iti o nal R esidue Data on Corn S tover. Summary of Residue Data. S. Funk D380050 02/13113 Metconazole: Response to Condition of R eg i s tration

- Storage S tabilit y Data for Triazole Me ta bolites in Pl ant Samples. S. Funk D40 3859 02 114/ 1 3 Metcon azo le : Amendment to Add D ry Bean , Sorg hum and S unfl ower as Rotated Cr ops with a 0-day Pl an t-b ack Inter va l ( PB! ) afte r Application ofCaramba , Multiva, or BAS 556 End-Use Products to Any of the Primar y Crop s Li s ted on the Lab e l. S ummar y of An a lytical C he mi s tr y and Re s idue Data

. N. Dodd D 4 1 9223 1 0/ 23/14 M e tc on azo le

. Petition for the Establishme nt of Permane nt Tolerances and R eg is trati o n for Use o n th e Pea a nd Be an , Dried S he ll ed, exce pt Soybean, Subgroup 6C and the Sunflower Subgroup 20 B; Expansion of the Canola Tol e rance to the Rap eseed S ub gro up 20 A ; a nd Conve rsion of th e Establis hed Sto ne Fruit and Tree Nut Crop Gro up s to the Sto ne F rui t Gro up 1 2 -1 2 and the Tree Nut Gro up 14-12. Summar y of Analytical C hemistry and Re s idu e Data. Dieta r y Ex p os ure As sess men t N. Dodd D4 23622 11 17/ 14 Metconazole Acute and C hroni c Aggregate Dietary (Foo d and Drinkin g W

ate r ) Exposure an d Ri s k Assessme nt for th e Secti on 3 R eg i s tra ti o n Action s on Pea and Bean. Dried Shelled , except Soybean , Sub g roup 6C and th e S unflower Subgroup 208; Expa nsio n of th e Cano la To lera nce to the R apeseed Subgro up 20A; and Convers ion of the Es tablished Stone F

ruit and Tree N ut Crop Groups to the Stone Fruit Group 12

- 12 and the Tree Nut Group 14-1 2. Occ upatio na l a nd Res ide n tia l Ex p os ure Ass ess me n ts K. Rury D4 23992 1211 1 / 14 MET CONAZOLE

. Occupational and R es id e nti a l Exposure Assessment fo r Proposed U ses on Dry S he ll ed Pe a a nd Bea ns (Except Soybea n) C rop Subgro up 6C and Sunflower Crop Subgro u p 20 8 : Crop Group Expan s ion to Rape see d S ub g roup 20A; and C rop Gro up Co n ve rsions to Fru it , Stone, Group 1 2 -12 ; an d Nut , Tree , Group 14-12. Also a R e-Eval uati on of a ll existin g R es id enti a l Uses of Metconazole. N. Tsaur D386786 06/ 08/11 Metco nazo l e. Occupationa l and R es id e ntia l Expos ur e Assessment fo r a Proposed New F ol iar Use on Sugarcane.



### P age I 2of27Recen t Me m o r a nd a Re leva n t to R e1? is tra t io n Rev iew o f Me tco n azo le A uth o r DPffX R # D ate Titl e N. Tsaur 0380989 02/ 03111 M e t

conazo l e. Occ upati o na l a nd R es id e nti a l Ex po s ure Ass e ssme nt for Pr opo se d IR-4 Foliar Uses on Oushberrics (Cro p Sub grou p 3-07 8 ) a nd Tuberous and Com1 Vege tables (Crop Subgroup IC). N. Tsaur 0 375763 02 / 03 / 11 Metco na zo l e. Occupational and Resid e ntial Exposure Assessment for Seed Treatment Use o n Barley. Ca no l a, Cotton, Oats , T ritic ale. Wheat , Com (Field , Swee t , and Popcorn) , and Suga r Beets. N. Tsaur 0 350368 09/ 22 /08 Metcona zo le. Occupational and Residentia l Exposur e / Risk Assess m e nt for Section 3 Use on Cano la. B. O ' Kecfe 0343433 08/ 20/ 08 Metconazole. Occ upati ona l and Residential Expos ure/ Risk Assess ment for Sec ti o n 3 Use o n Corn and Cotto n , a nd Se ction 18 Use on Sugarcane. J. Arthur 0 331932 10 / 18/ 07 Me t conazole: Occupational and Residential Exposure/ Risk Assessment fo r Use o n Pea nut , Stone Fruit, Tree Nuts, Barley, Oat s, Rye , Soy bean s, S uga r Beets, Triti ca le and Wh ea t. J. Arthur 0 341832 08.03 /07 Metconazole: Occupati o nal and Residential Expos ure/ Ri s k Assessment for Use on Ornamentals and Turf. I nc id e n t Re port S. Recor e 0428900 09/ 01 / 15 Me tcon azo le: Tier I R ev iew of Human I ncident s Tox ic o logy J

. Leshin TXR0057053 10 / 09/ 14 Metconazo lc: S ummary of Ha za rd a nd Sc ie nc e Pol icy Co un ci l ( HASPO C) Meeting of September 1 Ith , 2 0 1 4: Revisit for th e Requirement ofa Subchronic I nha lati on Study from the Jun e 19'h mee tin g K. Ru ry TXR0056405 08 /09 / 1 2 Metco nazo le: Su mmary of H azard and Sc ien ce Pol icy Co uncil ( HASPO C) Me etin g of Jul y 19 , 20 1 2: R ecom mend a ti o n s o n the R

equi rement or a Subc h ronic Inhalation Study and an Acu t e Ncuro toxic ity S tud y . M

. Copley 0329170 09 1 03 1 09 Mctcom1zolc: Correc t ed Appendix 3. Subc hronic, Chronic and Other Toxicity Profile Table for use in future Ri sk Assessme nt s for Metcona zo le

. J

. Kidwell TXR005421 I 04 1 14 1 06 METCONAZOLE: R eport o r th e Cancer Assessmen t R eview C omminee


### A ttachm e nt s I. Chemical Id e ntit y Table 2. Ph ys ico ch e mical Prop e rtie s of Techn ical Grade Metconazo le Table 3. Endpoint Selec ti o n Table 4

. Toxicity Profile Tables 5. Toxicology Data Requ irements Table 

### 6. To l era nce / MRL Table

P age 13 of27

### Attac hm e nt 1 C h emica l Identity Tab le
Tab l e 1. 

### Metconazole No m e n clatu r e. Chemical Structure

Com mo n na me

CAS name CAS ff Cl Cl cis-isomer 

### trans-i so m er Metconazole KN F- S

-474m (Ku r e ha); BAS 555 F (BASF); V- 10 11 6 (Va l en t ) ( 1RS , 5RS ; 1RS ,5S R)-5-(4

-ch lorobenzyl ) -2 ,2 -dimeth y l-1- ( 1 H

- 1 ,2, 4

-tri azo l- lilmet h l )c clo enta no l 5-(( 4

- ch lorophenyl)me thyl)-2,2-dimeth y l-1- ( l /

- /

- 1 ,2, 4

-tr iazol-1- ylmethyl)c clo e nt ano l 1251 1 6-23

-6 

### (cis

- and 

### tran s -isomers ) 11 5850-27

- 6 (cis

- isome r ) 115850-28- 7 

### (trans-isomer



### P age 1 4of27

### Attachment 2

Tab l e 2. P h ys icoc b e mi ca l Pr o p erties of Mctco n azo le P aramet er Value References• (MRID) Meltin g poinl/range I 00.0-108.4 ° C ( u s in g E l ec trothermal Digital Melting Point 44721505 Appa r atu s) (AC900,768 technical grade) pH 5.8 1 at 25°C ( I % aq u eous s usp e n s io n) 46808402 Rel at ive density (20°C) 1.14 ( relative den s it y to wate r at 4 ° C, using capillar y - 4472 15 05 s toppere d , den s it y-spec ific g r avity bo ttl e) (Lo t No. AC 8879- 1408 ) Water so lubilit y (20°C) Using s hake-na s k method: 44721505 18 .7 ± 1.0 m g / L ( c is-isomer, WL 148 27 1, KNF-S-474m) I 3.6 ± 1.7 m g/L 

### (1rans-isomer , WL 148 27 1, KNF-S -4 74m) Solvent so lubility (g/L) at So lvent Metconazole 

### ci s trans 44721505 20 °c acetone 363 251 117 methanol 403 294 117 dichloromethane 481 343 141 ethy l acetate 26 0 1 73 90.0 propanol 132 86.6 46.7 t oluene 10 3 66.2 38.0 Hexane 1.40 0.929 0.483 Vapor pressure (2 0 ° C) Using gas - s aturation m e th od: 44721505 < I .23x I 0.5 Pa o r 9.23 x I

## o· 8 mm H g ( metconazole) < 1 .04x I 

## o· 5 Pa or 7

. 80 x I

## o· 8 mm Hg ( c i s -isomer) < I

. 96x I 

## o- 6 Pa or 1.4 7 x l 

## o· 8 mm Hg (1rt1ns- i s omer) Di ssocia tion constant ( pK .) 11.38 ±0

. 03 and 1 .06±0.03 (i n water at 29. 1° C using 44721505 spectropho t ometric method ; Lot No. A C 8879 -1408 ) Octanol / water partition A t 20 °C (using fla s k shaki ng method}: 44721505 coeffici e nt , Log(K ow ) Knw ( log Kow) = 7090±989 (3.85) (Lot No. AC 8879-1408 ) (TGA I) K

ow ( log K ow) = 7150± 803 (3.85) (cis- i so mer, CL 354,80 I ) K

ow (log K o

,.) = 6800± 1700 (3.8) 

### (/rans-isomer, CL 354 , 802) UY / visible abso rption pH A. A log E 46808403 s p ec trum 

### cis -isomer 2.0 22 1 .4 0.828 4.03 6.8 0.8452 4.04 7.0 0.9126 4.08 1 0.3 0.7226 3.98 

### /rans -isomer

2.0 22 1 .4 0.9053 4.07 7.0 0.9547 4. 10 10.1 0.9893 4.1 1 

## * Product C hemi s try Review s: DP f/2 56877 , S hyam Mathur, Ph.D. , 9/ 12 /2000 and DP #32 9168 , S hya m Mathur , Ph.D., 7/ 1 3/ 07.



### P age 15of27

### Attac hm e nt 3 Summary of Toxicity En dp oint s and Points of Departure of Mctco na zo l e
Tab le 3.1. S umm a r y of Toxicologica l Doses a nd E ndp o int s for Metcona zo le for Use in Di etary a n d No n Occ up atio nal Hum a n H ea lth Ri s k Ass ess m ents Ex po s ur e / Point of Uncertaint y/FQPA RID , PAO , Level Stud y a n d Tox ico lo g ical Effects Sce nari o D epartur e Sa f ety Fac t o r s o f Concern for R is k As sess ment Acute Dietar y An appropr iate dose/ endpoint attributabl e to a si ngle d ose was not observed in the availab le ora l (Gene ral t oxicity studies r ev iewed

. Population , including Infants and Children) Acu te Dietary NOAEL= 1 2 UF A= IOX Acute RID = 0.12 De ve lopmen t a l to xic i ty in rat s: (Females 1 3-49 mg/k g/da y UF H

= IOX mg/k g/da y LOA EL = 30 m g/

k

g/day based on years of age) FQPA SF = IX incr eases in skeleta l variat i on s . At 75 aPAD = 0. 1 2 mg/kg/ day (the next hi g h e r do s e mg/ kg/day lev el) increa sed incidence of po s timplantation lo ss . hydrocephal y and visceral anomalie '.? a ( cranial hemorrhage, dilated rena l pe lvi s , dilat ed ur eters , and displaced t estis) were reported. Chronic NOAEL = 4.3 UFA= I OX Chronic RID = C h ronic oral t oxici t y s tud y in r a ts: Die tary (All m g/

k

g/day UF11 = I OX 0.04 m g/kg/day LOA EL = 13.1 mg/kg/day based on Popu lations) FQPA SF = I X incr eased li ve r ( M) weights and cPA D = 0.04 associated hepatocellular lipid mg/k g/day vacuolation (M) and centrilobular hypertrop hy(M). S imilar effects were obse r ve d in fema les at 54 mg/kg/day. plus increased sp l een weight. Incidental Oral NOAEL = 9.I UF A= IOX Residential LOC 28

- Da y ora l toxici ty s tud y in ra ts: Short-Term (I- mg/k g/day UF11 = IOX for MOE = 100 LOA EL = 90.5 mg/ kg/ day ba s ed on 30 day s) FQPA SF = IX decr ease d bod y weight (M), increased live r and kidney weight and hepatocellular hyp ertroph y a nd vacuola ti on (M / F). Incidental Oral NOAEL = 6.4 UFA = I OX R es idential LOC 90-Da y ora l t ox ic it y s tud y in rat s : Intermediate- mg/k g/day UFH = IOX for MOE = 1 00 LOA EL = 19. 2 based on increased Tenn ( 1-6 FQPA SF= IX spleen wt (F) and hepatic vacuolation months) (M). Derma l Short- Quantification of dermal r isk is not required due to l ack of sys temic or dermal toxicity at the Limit ( 1-30 da ys) & Do se in a 21 -d ay derma l toxicit y s tudy in th e ra t , the lack of ne ur otoxic ity , and th e lack of co ncern Int ermediate- for developmental , reproductive or neurotoxicity. Tenn (1

- 6 mon t hs) I nhalation NOAEL= 9.1 UF A= IOX Re s idential LOC 28-Da y oral t ox ic it y s tu d y in r ats: Short- Term mg/k g/day UFH = IOX for MOE = I 000 LOA EL = 90.5 mg/k g/da y ba s ed on (1-30 days) UF oo= IOX decreased body weight (M ), increased FQPA SF = IX liv er and kidney weight and hepa toce llul ar hype rtroph y and vacuo lat ion (M / F).



### Page 16of27Tab le 3. 1. S umm ary of To xi co l og ic a l D ose s and E nd poi n ts fo r M et co n a z o l c for U se in Di et a r y a n d No n Occ uo at i o n a l Hum a n H ea l t h Ri s k Ass ess m e n t s Expo s ure/ P o in t o f U n ce r ta i nty/ FQ PA RID , PA D, Lev e l S tud y a nd Tox ico log ica l E ff e ct s Sce nar io D e p a r ture S afety Fa cto r s o f Conc e rn fo r R is k Assess m e nt Inhalation NOAEL= 6.4 UFA= !OX Residential LOC 90- Day ora l tox ic it y s t u d y in r a ts: Intermediate- mg/kg/day UFtt=IOX for MOE = I000 LOAEL = 1 9.2 mg/kg/day based o n Term ( 1 -6 UFoo = I O X in c rease d splee n wt (F) a nd h epa ti c mon t hs) FQPA S F = I X vacuo lati o n (M). Cancer (oral , Classification: " Not like ly to be Carcinogenic to Humans" demrnl , inhalation )

P o int o f Dcpanurc ( PO D)= A da1a po 1111 o r an c s 111na1ed po int that 1 s deri ved fro m o bserved d ose-res po ns e data and us ed t o mark the bc g mnm g o f cx 1rapo la11 011 1 0 dctcnninc ri s k assoc iated wi1h lower environmentally relevant human exp os ure s . NOAEL = n o o b served adverse effe ct l evel. LO A E L = lowe s t o bs erved advers e effe c t leve l. UF = uncertain t y fact o r. UF,. = extrapo lat ion fro m anima l 1 0 human (i nters pec ies ). UFu = po tential var iati o n in sens i tivity among members of th e h uman pop u lmion (in tras p ccics)

. UFoo = to accoun t for the abse n ce of key data (i

. e .. ln ck o f a criti c al s tud y)

. FQP/\ SF = FQPA S afet y Factor

. PAD = pop ul mi o n ad j usted do s e ( a = acute , c = chronic)

. RfD = reference dose

. MO E = mar gi n of ex p os ure . l. OC = lev e l o f co n cern . NIA = not applicab l e .

T a b le 3. 2

. S u m ma r y o f T o xico log ica l Do ses a nd En d po in ts for Me t co n azo le fo r Us e in Oc c u patio n a l Hum a n H ea lth R is k Assess me n ts E xpo s u r e/ P o in t o f Un ce r ta inty Lev e l of Co n ce rn S tud y a nd Tox i co log i ca l E ff ects S ce n ari o Dep a rtur e Factors for Ri s k Ass e ss ment Dermal Short- Quantification of dermal risk is not requi red due to lack of systemic or dermal toxicity at the Limit ( 1

- 30 da ys) & Dose in a 2 1 -da y de rmal toxicity s tudy in t he rat , the lack of concern for deve l opmental , reproductive Intermediate- or neurotoxicit y . Tcm1 (1-6 months) Inhalation NOAEL= 9. I UF A= ! OX Occupationa l LOC 28

- Da y o r a l t ox ic it y s t u d y in r at s : Short-Term ( 1- mg/kg/day UFtt = IOX for MOE = I 000 LOAEL = 90.5 mg/ k

g/day based on 3 0 d ays) UF oe= IOX decreased body weight (M) , increa se d liver and kidne y weight and hepatoce ll ular hypertrophy and vacuo lati on ( M /f.'). In ha lati on NOAE L= 6.4 UF A

= IOX Occ upa tion a l LOC 9 0

- Da y o ra l to xi cit y s tud y in ra t s : I ntermediate- mg/kg/day UF11 = I OX for MOE = l 000 LOAEL = 19.2 mg/kg/day based on term ( 1-6 UF oe= I OX in creased spleen wt (F) and hepat ic month s) vacuolation (M). Cancer ( ora l , Classification: " Not Likely to be Carcinoge nic to H umans " dennal , inha lat ion) Po int o l Dcpnrturc (POD )= A da t a po m t o r an csu matcd po111 t lha t 1 s de ri ved from observed do se-respo nse darn and us ed t o mark th e bcg 1 n n111 g o f extrapo lat io n t o dete rmine ri s k assoc ialcd wi th l o wer cnviro11111c111<1ll y re l evan t h uman exp os ures . NOAEL = n o o b served adverse cfTcct level

. LOA EL = lo we s t o bse rved adverse effec t level. U F = uncenaint y fa ct o r . U F A= extrapo lati on fro m animal t o human ( interspecies ). U F

11 = po t e nt ia l vari at io n in se n sitiv i t y am o n g m embers o f the humru1 p opulati o n ( intraspeci es)

. U l7 00 = to acc ount for the ab sen ce o f ke y date ( i

. e .. lac k of a cri11ca l s tud y) MOE= marg in of e x pos ure . LOC = level o f co n cern . N I A= n o t appli cable

.



### P age 17of27

### Attac hm e nt 4 Toxicity Profi l e for Metco na zo l e
Table A.2 .1. Acute Tox i city P r ofile

- Metconazo le Tech ni cal G uid elin e No

. St ud y Type MRCD( s) Re s ults Tox i city Catego r y 870. I 100 Acute oral [mou se ] 44721512 LD so = > 566 mg/ kg III 870.1100 Acute oral [rat) 44721512 LD so = > 566 mg/ kg Ill 870. l JO O Acute ora l [ra t] 44721513 LD so = > 1 4 59 mg/kg Ill 870.1100 Acute oral [rat) 44721514 LD so = > 5000 rn g/ kg I V 870.1200 Acute dennal [rat] 44721512 Dermal LD so > 2000 111 870.1200 Acute dermal [rnbbit] 44721512 Derma l LDs o > 2000 Ill 870. 1 200 Acu t e inhalation [rat] 4472 1 5 1

2 LD so 

### = > 5.6 m g/L I V 870.2400 Acute eye irritation [rat] 44721513 moderate irritant III 870.2500 Acute dermal irritation [rabbit] 44721513 mi ld irritant IV 870.2600 Skin se ns itization [guinea pig] 44721513 neg. 

### - Tab l e A.2.2. No n-a c ut e Toxicity Profile for M etco nazo le

Tab le A.2 .2. S ub chronic , C hr o ni c and Ot h e r To xici t y Profile for M etco na zo l e Te c h ni ca l ' Gu i d e line S tud y T y p e MRJO No. (yea r )/ R es ult s No. C las s ifi ca tion / Do s es 870.3100 28-Day oral toxicity 44721515 (1990) NOA EL (M / F) 

### = 9.1 / 10 .1 m g/

k

g/

day rodents (rat) MlF: 0 , 30, I00, I000. LOA EL (M / F) = 90.5 / 97 mg/k g/da y based 3000 ppm on depression of body weight in M , liver M: 0, 2.7 , 9. 1, 90.5, 26 1.1 and kidney we ig ht in creases with mg/kg/day associa ted histopatho logical effects F: 0, 3. 1, IO.I. 97, 287.4 ( hypenroph y and fatty vacuolation) in li ve r mg/k g/day only

. Accep table/ guid e lin e 870.3 100 90-Day oral toxicity 44 721517 ( 1991) NOAEL (M / F) = 6.4/7.2 m g/k g/day rodents (rat) M / F: 0, 30 . I00. 300 , I000, LOAEL (M/F) 

### = 19.2 /22.1 mg/ k

g/da y 3000 ppm ba s ed on incr eased spleen weight in M: 0 , 1 .94. 6.4, 19.2 , 64.3, fe ma les and hepatic vacuo lation in ma l es. 192. 7 m g/k g/da y F: 0 , 2.1 , 7.2 , 22.1 , 71.4. 208.0 rng/k g/day Accep tab le / gu id eline 870.3100 90-Day oral toxicity 44721519 (199 1 ) NOAEL (M / F ) = 9.58 /6.94 m g/kg/day rodent s (mouse) MlF: 0 , 30, 300, 3000 (wk LOAEL (MlF) 

### = 50.5/ 60.7 mg/kg/da y l ) /2000(wk 2-13) ppm ba se d on incr ease in absolute and relativ e M: 0, 9.58, 50.5, 34 1

. I l iver weights, hepatocellular hypenrophy m

g/

k

g/day and vacuolation, an d increa se in relative F: 0 , 6.94. 60.7 , 438.5 s pleen weigh t (F), elevated AST and ALT mg/k g/ da y activity. Acceptable/ guideline



### P age 18 of27T ab l e A.2.2. S ub c h ro ni c, C hr o ni c a nd Other T o xicity Pr o fil e fo r Metc o n azo l e T ec hni cal 1 G uid e lin e S tudy T y p e MRID No

. (year) / Re s ults No. C l ass ifi cation / D oses 870.3150 28-Day oral toxicity 44721520 (1991) NOAEL (M / F) 

## = I00 ppm in diet non-rode nt s (dog) M/F: 0 , I00 , I 000, and LOA EL (M / F) 

## = I 000 ppm in diet ( in c rease 7000-10000 ppm in diet in relative and absolute thyroid wt. in Unaccep tabl e/ non- one/ rwo fema les) g uid e lin e (some Defic iencies: low n (2M/2F per do se); preliminary te s t data decrease in food consumption mean s low provid ed) exposure to test compound; actual do se r ece ived per dose g ro up not provided. 870.3150 90-Day oral 44721521 ( 1991 ) NOA EL (M / F) = 2.5/2.6 mg/kg/day toxicity non-rodents M / F: 0, 60, 600 , 6000 ppm LOA EL (M / F) 

### = 24.4 /24

. 3 mg/ kg/day (dog) in diet ba se d on decreased food con s umption in M: 0, 2.5 , 24 .4 , 225.2 females and elevated platelet s and mg/k g/day reticulocytes in males. F: 0 , 2.6, 24.3, 206.6 mg/k g/day Accep table/ guideline 870.3200 21-day Dermal 46808439 (2006) NOA EL: I000 m g/

kg Toxicity 0,250,500, 1000 mg/k g/day LOA EL: > I 000 mg/kg Acceptable /gu id e lin e No evidence of dermal toxicit y . 870.6200 Subchronic ( 13- 46808440 (2002) Sys t e mi c NOAEL (M / F) 

## = 4.84/ 5.10 week) Oral 0, 50 , 170, 500 ppm mg/kg/ Neurotoxicity- rat M: 0, 4.84, 15.69 , 47.08 Sys te mi c LOAEL ( M/F) 

### = 15.69 / 17 .62 mg/k g/day mg/ kg/ based on decreases in body weight F:0,5.10, 17.62,49.82 and food con s umption. m

g/

k

g/day Acceptable/Non-guidel in e Ncuro to xi c it y NOA EL (M/F)**~** 47.08/49.82 mg/k g/day 870.3700 Prenatal 4472 1522 (1991) Mat e rnal NOAEL 

### = 75 mg/kg/day development in 0, 1 2, 30, 75 m g/

kg/day LOA EL > 75 mg/ k g/day, not es tabli s hed. rod e nt s (ra t) Gavage Decreased body we ig ht gain was observed Acceptable/ Guide line at 30 mg/kg/day and high e r, upon which th e maternal LOAEL was based in previous risk assessments. However, body we i g ht gain c han ges without changes in absolu t e body weight are not current ly considered an adverse effect, so th e re is currently no maternal LOAEL.
D

eve lop m e n ta l NOAEL 

### = 1 2 m g/

k

g/day LOA EL = 30 mg/k g/day based on increased incidence of skeletal variations (p redominantl y lumbar rib s). At 75 mg/k g/day increased incidence of postimpl antati on los s, hyclrocephaly and viscera l anomalies (cranial hemorrhage , dilated renal pelvis , dilated ureters, and disp laced test is) were reported.



### Page 19of27Table A

. 2

. 2

. Subchronic, Chronic a nd Other Toxicity Profile for Metconazole Tech ni ca l 1 Gu id e lin e Study T y pe MRID No

. (year)/ Re s u l ts No. C lass ifi ca tion / Do ses 870.3700 Prenatal 46808443 (2002) Materna l NOAEL

- 16 mg/ k

g/

day developmen t in 0 , I , 4 , 16, 64 mg/ k

g/day LOAEL= 64 mg/k g/day ba sed on dec rea sed roden t s (rat) Gavage body weight and food co n sumption

. Acceptab l e/Guideline increa se d placental weight and increased incidence of s wollen placenta.

Deve lo pmental NOAEL = 16 m g/

k

g/day LOAEL= 64 mg/kg/day ba sed on based on an increase in early and late resorptions , decreased fetal body weight and increased incidence of in comp l e t

e ossification of s temebrae. 870.3700 Prenatal 44721602 ( 1997 ) Maternal NOA EL = 20 mg/kg/day developmental in 0, 5 , I0, 20, 40 mg/kg/day LOAEL = 40 mg/k g/day base d on non-rod ents ( rabbit) gavage r e duction in food consumption, and Acceptable/Guideline changes in various hematolo gy parameters D

e finitive Study (reductions in hematocrit , hemoglobin, mean corpuscular volume and increases in platelet counts and alkaline phosphatase ac tivit y).
Deve l opmental NOA EL 

## = 20 mg/kg/da y LOA EL = 40 mg/k g/ day based on increa ses in post-implantation losses. 870.3700 Prenatal 44721603 (1991) Materna l NOAEL 

## = 25 mg/ kg/day developmental in 0 , 4 , I 0, 25, 62.5 LOA EL = 62.5 m g/kg/day based on body non-rodents (rabbi t ) mg/k g/da y (Exp. ff I) weight c han ges and sl i gh t clinical s i gns 0, 2, 4, I0 mg/kg/day (Exp. (a norexia/red uced or altered fecal output, #2) co ld cars). Acceptable/ Guideline D eve lop me nt al NOAEL = 4 mg/kg/day LOA EL = I 0 mg/k g/ day based on exa mining data from the two experiments. Effec ts at 62.5 mg/kg/day s how total litt e r loss , d ecreased live fetuses. increa se d early and late resorption s. Effect s at 25 mg/kg/day show some malformations: hydroc ephaly (4 fetu s es from 4 different litters, but NOT see n a t 62.5 mg/k g/ day) and limb effects (2 fetuses from 2 different litters , with one fe tu s wi th sa me effec t at 62.5 mg/ kg/d). Hydrocephaly and limb effects were observed at I0 mg/k g/day in Experimen t #2

. but not at that same dose in Experiment ff I

.



### Page 20of27Table A.2.2

. Subc hro n ic, C hr o n ic and Other Toxic i ty Pro fil e for M e tco n azo le Tech n ica l 1 Guidel in e St u d y T y p e MRID No. (yea r ) / Resu lts No. C lass ifi catio n /Do ses 870.3800 Reproduction and 46808447 (2002) Parental/ Sys temic NOA EL (M/ F) 

### = fertility effects 0, 30, 150 and 750 ppm 9.8/ 10 .8 mg/kg/day 2-generation

- rat M / F: 0 1 0, 2/2. I0.8/10.6, LOAEL (M/F) 

### = 49.4 / 53.2 mg/kg/day 53.2/ 53.0 mg/kg/day based on: decreased body weight and Acceptable /Guideline dec r eased we i g ht ga in in male and female paren ta l a nimal s, in creased in cidence of fatty hepatocyte change in male parental animals, and inc reased incidence of spleen congestion in FI parental females.
Re p rod u c ti ve NOAEL (M / F) 

### =**~49.4 /**  I0.8 mg/k g/day LOAEL (M/F) = 53.2 mg/k g/ day based on increased gestation length and decreased gestation index driven by dystocia (d iffi cu lt l abo r). Offspri n g NOAEL (M / F) 

### = 9.8 / 10.8 mg/k g/ da y LOAEL (M / F) 

### = 49.4 / 53.2 mg/kg/day based d ec r eased v iab ilit y on lac tation d ay 0 and decr eased body weight in F2 offspring. 870.4 IOOa Chronic toxicity 4472109 (1992) NOA EL = (M / F) 

### = 4.3/16.0 mg/kg/day rodents (ra t) 0, I0 , I 00, JOO, I000 ppm LOAE L = (M/F) 

### = 13.1/ 53.8 mg/kg/day M:0,0.44 , 4.3, 13.1,43.9 based on an increase in mean ad ju s t ed liver mg/kg/day weights at 1 2 months (M) and 24 month s F: 0, 0.52, 5.3, 16.0, 53.8 (F), increase in sp lee n w eig hts at 24 months mg/kg/day (F), and increased hep atocell ul ar li pid Acceptable/ Gu id eline vacuolation (M / F) and cen trilobul ar hypertrophy (M/F). 870.41 OOb C hron i c toxicity- 4472 161 0 NOAEL (M / F) 

### = 12.0/10.3 m g/kg/day do g 0 , 30, 300, I 000 , 3000 ppm LOA E L ( M / F) = 38.5 / 36.8 mg/kg/da y in diet based on increased alkaline phosphatase M: 0, I.I , 12.0 , 38.5, 1 10.0 activity (both sexes) and increased mg/kg/day incidence of Kupffer ce ll pigmentation F: 0, I.I , 1 0.3, 36.8, 113.7 (females). mg/ k g/d ay Accep t ab le / G uid e lin e 870.4200a Carcinogenicity

- 44721611 ( 1992) NOA EL (M / F) 

### = 4.6/ 16.6 mg/kg/day rat 0, I00, 300, I000 ppm LOA EL (M / F) 

### = 13.8 / 56.2 mg/kg/day M: 0 , 4.6, 13.8, 46. 5 ba se d on non-neoplastic findings of mg/kg/day increa sed in cide nc e of hep atoce llul ar lipid F: 0, 5.5 , 16.6, 56.2 vacuo lation (M/F), cen trilobular mg/k g/da y hypertroph y (M / F), liver pigment Acceptable/Guideline deposition (M), histiocytic foci in the s pl een (M / F),and increase in severity of chronic re na l nep hrop ath y (M). Ev id ence of mon o nucl ear ce ll leukemia (17).



### Pa ge 21 of27Ta bl e A. 2 .2. S ub c hro ni c, C h ro ni c and O ther T ox i ci ty P r o fil e fo r Metco n azo l e Tec hni ca l 1 Gu id e lin e St u dy Type MRID No

. (yea r )/ Res ults No. C lass ifi ca ti on /Doses 870.4 2 00b Ca rcino genicity

- 44721612 ( 199 2) NOA EL (M/F) 

## = 39.5 / 5 .9 mg/ k

g/day mo use 0, 30 , 300 , 1 000 ppm LOA EL ( M / F) 

## = 166.9 / 58.1 mg/k g/da y M: 0, 4.5, 39.5, 166 .9 based o n non-n eop las tic findings of an mg/kg/day inc rease in corticom edullary pi g ment a tion , F: 0 , 5.9 , 58. 1 , 1 95.5 s inus o idal h y perce llularit y /s in g le cel l mg/k g/day necrosis. Neo pl a s tic findings: increase in Acceptable/Guide! ine liver ce ll tumor s at hi g h d ose ( M / F): Incr eased incidence of hepatoce llul ar adenomas in ma le s a nd hcp a t oce llul ar carcinomas in females. 870.5 100 Sa lm onella 44 72 161 3 ( 1990 ) Te s t material wa s not cytotoxic with o r t yphi11111ri11111 a nd Up to limit do se of 5000 without S9 activation in fi ve S. Es c herichia coli**~1 g/**  pl ate (S. typhi11111ri11111) t yphi11111ri11111 s train s and one s train of£. Reverse Mut ation and (£. co li) in th e co li , and did no t induce a ge no t oxic A

ssay pre se nce an d abse nc e of response in an y s tra in. metab o lic activation (± S9) Acceptable /Guid e line 870.5300 I n vitro Mouse 44721615 ( 1991 ) Th e re wa s no evidence of bio logically Lymphoma S ix doses up to 1 25 μg/ ml s ignificant induction o f mutant colonies. Mutag enes is Assay ( toxicit y was ob se rv ed WLl36184 • above th at dose) in the pre se nce and absence of •cis o nl y i so mer metabolic activation (± S9) Acceptable/ Guideline 870.5375 In vitro Cytoge neti cs 44721 6 16 ( 1991 ) Weakl y pos iti ve (ind uc ed chr o mo so me Test From 6.25 to 400**~1g/ml,** abe rrat io ns in Chi nese ham s ter ovary cells) with and without metabolic in th e pre se nce ofS9 activa ti o n, ne ga ti ve ac ti va ti o n (± S9) without S9 activation

. Ac ceptab le /Guideline 870. 5395 In vivo Mamma li a n 447216 18 ( 19 95) There was no s ta ti s ticall y s ig nificant E

r yt hrocyte Up to th e limit dose of increa se in the freq uen cy o f micronucleated Micronucleus Tes t : 2000 m g/

kg pol yc hro mati c erythrocytes in mou se bone Mouse A cc ep tab le/ Guideline marrow at a ny dose or collectio n time. 870. 555 0 In vivo/ in vitro 447216 2 0 ( 199 5) Negative for un sc heduled DNA syn th es is. Mamma li an U DS U p t o th e limit dose of test 2000 mg/ kg Rat Accept able/Guid e line 8 70.6200 b S ubchron ic 46808440 (200 2) S ys temic NOAEL ( M / F

) 

## = 4

. 84 / 5. 10 Neuroto xicity- rat 0, 50 , 170. 500 ppm m g/k g/ M: 0 , 4.84, 15 .69, 47 .0 8 Sys t e mi c LOAEL ( M /F) 

## = 15 .69 1 17.62 mg/kg/d ay m g/kg/ ba sed o n decrea ses in bod y we ig ht F: 0 , 5. 1 0, 1 7.62 , 49.82 and food consumption. mg/kg/day Acceptabl e /Non- g uideline Ne ur otox ic it y NOAE L (M / F) ;o: 47.08/49.82 mg/k g/da y (Ac ut e ne urot oxic ity study ha s been waived)



### Pa ge 22 of27T a b l e A.2.2. S u b c hro ni c, C hr o nic an d O t h e r Toxicity Pro fil e for Mc t co n azo l e T ec h n ica l ' Gu i de li n e Study Type MRTD No. (year)/ Res u l ts No. Class i ficat i o n /Doses 870.7485 Metabolism a nd 4472 1 622 ( 199 2) Approximately 94% of radioactivity in pharmacokinetics: single high dose: 164 excreta afler five days: fece s (males

- rat mg/kg 81.3 %, females

- 65.5%) and urine (males

- Radiolabel: 13.6 %, females

- 28.4%) (cyclopentyl

14 C) Acceptable/ Gui deline 870.7485 Metabolism and 4472 16 23 (1991) Approximately 94% of radioactivity in pharmacokinetics: sing le low dose: 2 mg/kg excreta afte r 72 hrs: feces (ma les - 80 %, rat Radiolabel: females

- 67%) and urine (males

- 14.8 %,**(cyclopentyl-'~C)** females

- 26%). Metabolite information Acceptable /Guideline presented. 870.7485 Metabolism and 44721624 ( 1991) Approximately 96% of radioactivity in pharmacokinetics: single high dose: 200 excreta after seven days: feces (76%) and rat mg/kg (ma les only) urin e (20%). M e tabo lite information WL136184• Radiolabel: presented. •cis only isomer (T riazol e - HC) Acceptable/Guideline 870.7485 Metabolism and 44721625 ( 1991 ) Excretion / retention in bil e-duc t cannulated pharmacokinetics: s ingle low dose: 2 mg/kg rats. Approximately 80 % of radioacti vity rat Radiolabel: was excreted in the bile after 48 hrs: males WL136184* (Cyc lop entyl

- 14 C) (78.7%) a nd females (83.3%). *c is only isomer Acceptable/ Guideline
870.7485 Metabolism and 46808449 (2002) Low potential for bioaccumulation pharmacokinetics: male/ fema l e rat following sing le or multiple dosing rat s ingle low dose: 2 mg/kg regimen

. The tim e to maximum pla sma s ingle high dose: 200 concentratio n for male and female rat s mg/kg treated with either 2 mg/kg or 200 mg/kg repeated dose: 2 mg/ kg was the earliest sampling interval, 0.25 Acceptable/Non-guideline hours and 4 hours, respective ly The plasma half-life of low- and high-close rat s was s li gh tl y s horter in males than females , - 20

- 25 hours and

- 34 hours , re s pectivel y . 870.7600 In Vivo Dermal 46808450 ( 199 0) Dermal absorption = 16% (72 hrs) Penetration Stud y Acceptab lc/N on-guide I inc 870.7800 lmmunotoxicit y 48107301 (2010) Systemic Study: male rat NOAEL: 52 mg/ k

g/day. 0, 70, 2 10. 6300 ppm LOA EL: > 52 mg/kg/day 0, 5.4 , 17 , 52 m g/k g/day l mmunotoxicity Acceptable/ Guideline NOAEL: 52 mg/ kg/ day. LOAEL: > 52 mg/ kg/day



### Page 23of27Tab le A.2

. 2

. S ub c hro ni c, C h ro ni c a n d Oth er T ox i cit y Pro fil e fo r Me t co n azo le Tec h n ica l 1 G uid e lin e S tud y Ty p e MRID No. (yea r )/ R es u l ts No. C las s ifi ca ti on /D o ses Non- Effects o n r at/mi ce 4 472 16 26 ( 19 9 1 ) In c reased li ve r we ig ht , cytoc h ro m e P 450, guide line li ve r enzymes 0 , 300 p pm in diet (mice) ethoxycoumarin 0

- deethyla se . WLl 36 1 84* a nd 0 , I000 pp m in di e t eth y lmor ph in e N- de methy lase, a nd laur ic (rats) fo r seven or 28 days acid 11

- hydrox y lase in both rats and mice. *c is o nl y iso mer Acce pt abl e/No n -guid e lin e No eff e ct o n eth oxy rcso ru fi n 0

- dcethyla s e . pa l mitoy l-CoA oxidation, or peroxisome p rol if era ti o n ( in te rms ofperoxi so me number or morpho logy)

. N

on- 1 4-day M ec ha ni s ti c 466654 0 3 (2004) In c r ease d li ve r we ight (300 and I 000 pp m ); guideline S tudy 0 , 30, 300 , I000 ppm in increased hepatic dru g metabolizin g di e t ( mi ce) for 1 4 d ays. e nzy m es (300 and I000 p pm ) after 7 day s; F: 4.5, 48 , 151 mg/k g/day enlarged livers (I 000 ppm) at day s 3. 7 and A cce pta bl e /No 11 -gz 1 id

e line 1 4; he pa ti c hypert rophy a nd vacuo lat ion (300 a n d 1000 pp m ) at day 1 4 ; i ncreased A L T and AST ac ti vit ies at I 000 ppm (day 14 ); inc r eased lip id perox i de (300 and 1000) at day 14 ; inc reased PCNA labeling a t 1 000 pp m at day 3 a nd 7. 1 c is / tr an s rati o is 85: 15. A ll s tud ies used c i s/r

ra ns mi xtur e unl ess o th er wise no t ed

.



### Page 24 of27

### A ttachment 5 

### Toxico l ogy Data R e quirem e nts
The requir e m e nt s (40 CF R 158.500 ) for foo d uses of metcon azo le are in the table below. Use of th e new gu id eli ne numbers does not impl y that 

### th e new ( 1998) guideline protoco ls were u sed.

T est Tec h n i ca l Required Sa ti s fi ed 870. 11 00 Acute Ora l T oxic ity ...... ... .......... .. ................ ..... ............ ye s yes 870.1200 Acu te D er mal Toxicity ...... ........ ............ . ..................... .. yes yes 870.1300 Acute Inh a lation Toxici t y . ....... ............... .... .. . .......... ... .. yes yes 870.2400 Primary Eye Irritati on . .. .. ......... ........... ....... ......... . .. ... . .. . yes yes 870.2500 Primary Derma l Irrit a tion

... . ......................... . ... ... .......... ye s yes 870.2600 Dermal Sensitization

....... ....... ............... . ..... . ............. ... . yes yes 870.3100 Ora l Subchronic ( rod ent)

.......................... ... ............ ..... ye s yes 870.3150 Ora l S ub c hronic ( n o nrod en t )

..... .......... . .. .. . .. ... . .... ....... . . yes yes 870.3200 21 -Da y Dermal.

. .. .......... .. .... ..... ........... ... .. .. .............. .... . yes yes 870.3250 90 -Da y Derm a l

.............................................................. no 

# -- 870.3465 90 -Da y Inhalation

................................. ....... .......... . .. .... yes no * 870.3700a Developmental Toxicity (rode nt)

............ .... .................. yes yes 870.3700b D evelopmental Toxicity (nonrodent)

......................... . .. yes yes 870.3800 Re product ion

... .. . . ................ .... .............. ..... ............. ...... yes yes 870.4 1 OOa C hronic Toxici ty ( rode nt)

......... ... ............ ...... ... . ............ yes yes 870.4 1 OOb C hronic Tox icity ( nonrode nt)

......... ..... ................... .. .... yes yes 870.4200a Oncogenicity (rat)

............. .... ................. ..... ............ ...... yes yes 870.4200b O nco genic ity ( mou se)

.... .. ...................... .. .................. . .. yes yes 870.4300 C hronic/Oncoge ni c ity

. . .. . ..................... ... ................. ..... yes yes 870.5100 Mutagenicity

- Gene Mutation

- bacterial

.... ........... .. . .. yes yes 870.5300 Mutagenicity

- Gene Mut a tion

- ma mmalian

............ ... yes yes 870

. Sxxx Mu tagenici ty-S tructura l C hrom oso mal Aberrations

.. yes yes 870.5xxx Mutagenicity - O th er Ge notoxic E ffects

.. ............... ... .. yes yes 8 70 .61 OOa Acute De layed Neurotox. (hen )

..................................... 11 0 no 870.6100b 90 -Da y Neuro toxicit y (hen)

.......... .. . ........................... .. no no 870.6200a Acute Ne urotox. Screening Baner y ( r a t

)

.... . . ..... . ...... ..... yes waived** 870

. 6200b 90- Day Neuro. Screen in g Battery (rat)

........... ...... ........ yes yes 870.6300 Develop. Neuro

........... ........ ...... .......... ........ ........ .......... no no 870.7485 General Metabolism

......... .... ..... ................................. ... yes yes 870.7600 Dermal Pene tration

................... .. ............................... .. . no yes 870.7800 lmmun otoxicity

.. ......... .... . ....... ...... . .................. . ............ yes yes Specia l S tudi es for Ocular Effects Acute Oral (rat )

......................................................... . no no Subch ronic Ora l ( rat)

......... ......... .......... ...... . ..... ...... .... no no Six -month Oral (dog)

......... . ....... . ................... ... ... .... .. n o no * TXR0057053, J

. Lesh in , I 0 1 09 1 20 14 waiver n o t granted ** TXR0056405, K. Rury , 08/ 09/2012 waiver g ran ted



### Page 25of27

### Attac hm e nt 6
To l c r a n cc / M RL T ab l e
Metco n azo l c (125 6 1 9; D a te o f R e qu es t 8/3/ 1 5) S um mary of US a nd Inte rn a ti o na l To le ra nces a nd Max imum Res idu e L imi ts R es idu e D e fin i tio n: 

# us Ca nad a Mex ico ' Co d ex 40 C FR § I 80 .6 I 7(a) General. 5 -[ (4

- chloropheny l ) meth y l]-2.2- 

### No n e Metconazole [5-[(4

-ch lorop henyl)methyl)- dimeth y l- I -(I H-1 ,2, 4-triazol- I2 ,2 -d im e th y l

- I -( 1 H-1 ,2,4- tri azo l

- I

- y lmeth y l) cyc lop enta no l y lm eth y l )cyc lo pentanol] as the sum of its 

### cis

- and 

### tran s -i so mers Co mm od it

y Tole ran ce (pp m) ! Max imum Res idu e limit ( 111 $!/kf.{) 

# us Canada Mexic o' Codex Almond, hull s 4 .0 Ban ana 2 0.1 0. 1 B ar l ey, grain 2.5 2.5 B arley, ha y 7.0 Barle y, s traw 7.0 Bee t , s ugar, dr ied pulp 0.70 Bee t. s ugar. molasses 0.08 Beet , sugar, root s 0.07 0.15 B us hb e rry s ub g roup 1 3-07 B 0.40 0.4 Catt le , meat by product s 0.04 0.04 Corn, field , forage 3.0 Co rn , field , gra in 0.02 0.04 Co rn , fie ld , s to ve r 30 Corn, pop, g rain 0.02 0.04 Co rn . pop , s tove r 30 Co rn , swee t , forage 3. 0 Corn, s weet , k e rnel plu s cob 0.01 0.04 with hu sks re moved Corn, sw eet , s tov er 30 .0 Co tt on, g in b yproducts 8

.0 Co tt on, und elinted seed 0.25 fa.£!. 0.04 0.04 Frui t , s ton e, gro up 1 2 -1 2 0.2 0

. 2 Goa t , meat by product s 0.04 0.04 Grain , aspirated g rain fractions 7.0 Horse, m eat b yproduct s 0.04 0.04 Nut, tree , group 14-1 2 0.04 0

.04 Oat , g rain 1.0 I Oa t , hay 17 Oa t , s traw 6

.0 Pea and bean , dried shelled, 0.15 0. 15 except soybean, subgroup 6C Peanut 0.04 0.04 Peanu t , refined o il 0.05 0.05 R

apese ed s ub g roup 20A 0 .0 8 0.08 Rye, grain 0.25 0.25 R

ye, st raw 1 4



### P age 26 of27

### S ummary of US a nd Int e rn atio na l To le ra nces and Maximum Residue L i mits 

### Res idu e De fi n itio11 : 

# us Ca nada Sheep, meat byprod u cts 0.04 0.04 Soy b ea n , forage 3.0 Soybean, h ay 6 .0 Soy bean , hull s 0.08 Soybean, seed 0.05 0.05 S u ga rca ne , ca ne 0.0 6 Sunflower subgroup 208 0.7 V ege t ab le , tub e rou s and corm, 0.04 0.0 4 subgro up IC Wheat , g rain 0.1 5 0.15 Wheat, ha y 16 Whe a t , mill ed byproduct s 0 .20 Wheat s traw 18 

### MRls with 

### NO US Equival e nt Fat of cattle 0.04 Fat of l).oa t s 0.04 Fat of ho gs 0.04 Fa t of hors es 0.04 Fat of pou ltry 0.04 Fa t of s heep 0.04 Meat of can l e 0.04 Mea t of goa ts 0.04 Mea t of hog s 0.04 Meat of horses 0.04 Meat of poultry 0.04 M ea t of s he ep 0.04 Milk 0.04 Co mpl e t ed: M. N eg u ssie; 8/ 12 / 15 1 Mexico adop t s US t o lerances and/or Codex MRL s fo r it s export purpo ses. 2 No U.S. regis tr ation as of Augus t 30 , 2 006.



### Page 27of27 Mex ico • Codex