### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D

. C

. 2 0460

MEMORAN D UM Da t e: 26

- AUG

- 20 1 5 OF F ICE OF C HEMI CAL SA FE TY AND P O L LU T IO N P R EVE NT ION



### SUBJECT : Tetraco n azo l e; Hum a n H ea lth Ri s k A s sess me nt S c o pin g Docume nt in Support of Re g is tration R e view

. PC Code: 1 2 060 3 Decision No.: 5 032 04 Peti tio n No.: N A R i s k Assess m ent Type : Sin g le Che mi ca l / Agg re gate TXRNo.: NA 

### MRID No

. : N A 

### DP Barco d e: D4 2 670 2 Reg i s t ra t io n No

. : N A Reg ul atory Acti o n: R eg i s tr at io n R ev i ew Sco pin g D oc um e nt Case No.: 704 3 CAS No.: 1 122 8 1-77

- 3 

### 40 CF R : § 180 FROM: An war Y

. Dun ba r, Ph

. D .,

# Ph**rrn ~~** **og ~**  Th o m as Bl oe m ,**Ch mis** **~ ~**  

### J ames Mill e r, E nv iro nm e nt a l Sc ie nti s t Ri s k A ssess m e nt Branch I ( RAB I ) H ea lth Effe ct s Divi s io n ( H E D ; 7 50 9 P)

TO: V e ro ni ca Du tch Ri sk Rev i e w M a na ge r Pesti c id e Re - Eva lu ati o n Di v i s io n ( PRD , 7 5 08P ) A tt ac h e d is H E D 's hum a n hea lth ri sk assess me nt sco pin g do cume nt fo r t e traco n azol e to s up po rt Reg ist r at ion Rev iew .

Page I of29Tctraconazo le Scoping Document DP # 426702


### Table of Co ntents 

### Exec utive S ummary ..... . .. ..... .. .... .. ................................. .- .............................................................. .. ..... . ..... .. . 3 1.0 Hazard ldentificationfroxicology

......................................................................................................... 5 2.0 R esi du e Che1nistry

.......................................... .... ... .. ...... ...... .. .. ..... ..... .. ..... .. .. . . ....................................... 6 3.0 Di etary Exposure

.. . ................................................................................................ . ..... .. ..... .... .... .. ......... 7 4.0 R esidential Exposure

.... .. ................................................................................................ . ..... .. ... .... . .. . .. .. 7 5.0 Agg r ega te Ri sk Assessment

.. ..... ... .... ... ...... . .......................................................................... .. . .. . .. .. .... .. 8 6.0 Occupational Exposure

.. .. ..... . ...... .. ..... .. ................................................................................ ... ... .. ..... .. . . 

## 8 7 .0 Pu b li c Hea lth and Pes ticid e Ep id emio lo gy Data

.. . .... . ..................... .. ..... .. ..... ..... .. ..... .. .... .... ... . .. . ... . .. . .. 10 8.0 Human Incident Dat a: OPP ID S (2012)

............................................................................................. 11 9.0 Tolerance Assessment and International Harmonization

.................................................................... 12 1 0.0 Environmental Ju s ti ce . . ...... .. . ... . .. .. ... . . .. .. ...... .. .......... ...... .. ...... .... ... .. ..... ... ..... . ........ .. .. . . .. ..... .. .. . . .. ..... .. 12 11 .0 Cumulative

............. . .. .. .. . .. .. ..... .. ...... .. ..... ... ..... ... ..... .. ............................ .. ..... .. ..... .. ..... .... .... .. .............. 12 12.0 Hurnan Studies

.................. . ...... . ...... .. ..... ... ..... ... ..... ... ..... .. ..... ... ..... .. ..... .. .. . .. .. . .. .. ..... . .. . .. ..... . ............... 12 1 3.0 Data Req uire m e nt s Required Und er Registration Review

....................................................... .. ....... 13 14.0 References

...................................................... . ....... . ...... .. ...... . ...... .. ..... .. ..... ... .................................... 1 3 15.0 Attac hn1 ents8

........................................................................................................... .. . .. . ... . .. . ..... .. . .. 15 A tt ac hm en t 1: Te tr aco nazole and I ts Metabolites Chemical Identity Table

............ . ............................... 16 Attachment 2 : Tetraconazole Endpoint Se l ection and Toxicity Profile Tabl es for Tetr ac on azo le Technical.

.... .. .. . .. .. .. . .. .. ..... .. ........ . ...... .. ..... .......... ......................................................... .. ..... .. . . .. .. ..... .. . . ... . . . 17 Attachment 3: 

### Registered End-Use Products and A p plication Scenarios /Rates (informat ion provided by BEAD)

.. .. ................................ . .. . ... . .. .. ..... ... .. . .. ... .. ..... ... .. . .. ...... .. ............. . ...... . ...... . . .. .. .. . .. . ... . .. . ..... . ...... .. .... 26

. : ...

Page 2 of29

### Tetraconazole Scoping Document DP# 426702


### Executive Summary HED has prepared a scop in g document to support the Reg istration Review of tetraconazole, (1-(2-(2 , 4- dichloropheny l )-3-( 1 , 1 , 2 , 2-tetrafluoroethoxy)propyl]-1 H-1,2 ,4- tri azole). Tetraconazole, a conazaole containing compound , is a pesticide chemical belonging to the class of chemicals known as th e triazol e fung icides wh ich inhibit fungal cell wa ll synt hesis and function. Tolerances for residues of tetraconazole are estab li shed under 40CFR§180.557 in/on a wide variety of crops at level s ranging from 0.03-1.0 ppm. Tolerances for residues of tetraconazole are also established in/on hog , poultry, and ruminant commodities at 0.01-0.25 ppm. The toxicity database for tetraconazole is complete a nd adequate to s upport Re g istration R ev iew requirements. The newly subm itted cancer mode-of-action data ha s been reviewed and based on the acceptable mitogenic mode of action for the liver tumors in mic e, t etraconazo le is classified as "not likel y to be carcinoge ni c to hum a n s at levels that do not cause increased cell proliferation in the liver" and a non-linear approach will be u sed for quantification of human canc e r risk

. Thi s meth odo lo gy u si ng the chronic reference dose (RID) wi ll adequately account for all chronic toxicity effects, including carcinoge ni city, like ly to r esult from exposure to t e traconazol e. For future actions, the non-can cer endpo int s and safety factors for tetraconazole w ill need to be re-evaluated and updated based upon current policies. Provided th e registered lab e ls are consistent with th e labels submitted to HED for revi ew and conform to a n y of the revisions requested by HED, adequate metabolism (crops , livestock , and rotational crops) and magnitude of the r es idu e data are available to su pport the registered u ses (no additional residue chemi s try data is required are needed; current tolerances are adequa te). Adequate methods are available for enforcement of the curren tly es tabli s hed tolera nces. The most recent acute and chronic dietary exposu r e analyses were conducted in 20 11 usin g the Dietary E xposure Evaluation Model

- Food Consumption Intake Database (DEEM -FCID , ver. 2.03) which incorporated food cons umpti o n data from the United States D epartmen t of Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). The unr efined acute analysis and r efined chronic a naly s i s (refined u s in g data from the processing, field trial , and feeding s tudie s and projected p e rcent crop treated estimates) resulted in exposure estimates which d id not exceed HED's leve l of concern**(~1.8%** 

### acute populati on-a djusted do se (aPAD );**.** 

### 9% c hronic populationadjusted do s e (cPAD) ; considered food and water). As part of Registration R eview , a revised dietary risk a s sessme nt may be necessary to reflect potential rev i se d es tim a t ed drinking water concentrations ( EDWCs) , the most recent dietary exposu re models , increased tolerances as a result of harmonization , and/ or revised toxicolo gica l points of departure ( PODs ). There a r e no r eside ntial uses proposed or currently reg i ste red for tetraconazole. Therefore , a re sidential handler and post-application exposure assessment is not needed to support Registration Review. Residential expos ures res ultin g from off-site transp o rt (e.g. , spray drift or volatilization) may occur as a res ult o f applications of tetraconazole. The need for spray drift and volatilization risk asse s sments for t e traconazole will be examined during R egistrat ion Review. In accordance with the Food Quality Protection Act (FQPA), HED must co nsid e r and aggregate (add) p e sticide exposure s and risks from three major sou rces: food , drinking wa t er, and residential exposu res.

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### Because there are no residential u ses for te traco n azo l e, o nl y foo d and wate r were included in prev iou s agg regate assessments. There is suffic ie nt in fo rm ation availab l e to assess aggregate exposure; therefore , a new a ggregate risk assess m e nt will be required during Regis trati o n Review to in co r porate rev ise d dietary expos ure analyse s . App li catio n o f tetraconazole also r es ult s in potential expos ur es to the m e tabolit es T (1 ,2, 4-triazole) , TA (tri azo ly lalanin e), T AA (tr iazolylacet ic acid), and T HP (t riazolyl h y drox ypropionic acid). These compounds are cons id e red to be tox icol og ic a lly different from te tracon azo le . HE D rece ntl y conducted an agg regate ri sk a sse ssment for these co mp ounds wi th the res ulting exposure estimates le ss than H E D 's le ve l of concern (0426493, 

### T. Morton, 9-Apr

- 20 1 5). F inall y , application of tetracona zo l e r es ult s in ex po s ure to other m e tab o lite s which HED has d e te rmined are toxicologically identical to propiconazole (M 14360-ketone , M 14360-CP(C-1 )

- alco hol, and M 14360(C-l )

- alcoho l). H E D h as previou s l y conc lud ed that the propiconazole ri s k assessments , which yielded expos ures J ess th an HED ' s level of co nc ern, did not require re v isi o n as the residue estimate s incorporated into these ana lys is we re protec tiv e of th e p ote nti a l re s idue s res ultin g from the application of tetraconazol e . As part of regi s tration review , revi se d tri azole and propiconazole risk assessments ma y be req uired. HED ha s co ndu c ted occupational h an dl er assessments fo r m ost of the occupational handler sc enario s ant ic ipate d for the regist ere d u ses o f tetraconazole. However, durin g Regi s trati o n R ev iew, updated occ upati o nal assess ment s w i ll be conducted to reflec t a ll currently r egiste r ed u ses, using current occ upational handler and po s t-application expos u re policie s an d/o r updated toxicological PODs as nee ded. The fo ll ow in g data deficiencie s w e re id e ntifi e d for t etraco n az ole:

• Tox icology: None • R es idu e Ch e mi s tr y: Pro v id ed th e re g i s ter ed label s are consistent with th e lab e ls submi tted to H E D fo r re v iew and co nform to any of the r ev is ion s re qu es ted by H E D , no additional res idu e c he mi s tr y d a ta are requi red. • Occupational Exposu re -ORE: A D FR ( di s lodgcable fol iar re sidu e ) s tud y is required (OCS PP Guideline # 875.2100). In addition , E PA ant ic ipates co ndu ct in g the fo llo w in g risk assess m e nt upd ates during Re g is tration Revi ew:

• Toxicology: Reevaluate tox icity e ndp o int / dose se le c ti o n , a lon g with th e FQP A Safety Factor (SF) based o n current HED p olicy. • Di etary Exp os ure: A r evised di e ta ry expos ure analy s is m ay b e re quired to re fl ec t th e most r ece nt dietary exposure mod e l s, p o tential rev ised E DWCs, and/o r change s to th e toxicological PO D s. • The need for sp ray drift and vo lati li zatio n ri sk assessme nt s for te traco nazo le will b e examined during Reg istration Rev ie w. • Agg regate Ex po s ure: Revi sed aggre g ate exposu re analyses may b e r e quire d to reflect revised dietary e xp os ure es tim ate s a nd /o r ch a n ges to the toxi co lo g ical POD s . • Occu p atio n al Exposure: R ev i sed occupat io n a l h andle r and po s t-applicati on de nnal and inhalation assessme nt s to re fle c t all potentia l expos ure scenarios , as well as updated policies and exposu re data , a nd updated toxicological P O D s if revised, and D FR data.

Pa ge 4 of29Tetraconazolc Scoping Document DP # 426702


### 1.0 Haza rd Id e ntifi cat i o nffoxico l ogy Tetraconazole is a systemic fungicide and a member of the conazole/ triazole class of pesticides. It inhibits fungal sterol production by inhibiting the enzyme lanosterol 14 a-demethylase, a cytochrome P450 enzyme. Thi s lead s to abnormal fungal cell wall production and function. The liver and kidney are the primary target organs of tetraconazole in all spec ie s in oral toxicity stud ie s of subchronic and chronic durations. Based upon newly submitted 

### in vivo cancer mode-of-action data in mice, the Agency has concluded that liver tumors observed in tests with that species are due to activation of the constitutive androstane receptor (CAR) in the liver (Rowland el 

### al., TXR # 0056628, April 02, 2013). ln the acute neurotoxicity study, loss of motor activity in both sexes , and clinical s ign s including hunched posture, decreased defecation, and/or red or yellow material on various body surfaces were observed in females. Th ere was no evidence of immunoto xicity or neurotoxicity following subchronic exposure. There were no systemic effects observed in the 21-day dermal toxicity study up to the highest dose test e d. Tetraconazole did not show evidence of mutagenicity in 

### in vitro or 

### in vivo studies. Jn contrast to the oral stud ie s where the most sensitive effec ts were in the liver and kidne y, inhalation exposure of tetraconazole to rats resulted in portal of entry effects including ; squamous ce ll metaplasia of the lary ngeal mucous, mono-nuclear cell infiltration , goblet cell hyperpla s ia , hypertrophy of the nasal cavity and nasopharyngeal duct, and follicular hypertrophy of the thyroid in males. At the highest co nce ntration tested , th e re were treatment-related increases in absolute lung weights in both sexes. Oral rat and rabbit prenatal developmental studies showed no evidence for increased quantitative s usceptibility of the fetus to tetraconazole exposure 

### in ulero. 

### Developmental effects were se en in the presence of maternal effects in rats , while no developmental effects were seen in rabbits

. A twoge n e ration rat reproduction study also revealed no evidence for increased quantitative susceptibility in offspring. Decreased li tter and mean pup weights and increased liver weights were noted in offspring at a dose hi g her than that which caused mortality in adult females. Effects in parental animal s that s urvived the duration of the s tudy were consistent with ot her stud ies in the database. Tetraconazole has low acute toxicity via the oral , dermal , and inhalation routes (Categories III and IV). It is a slight eye irritant (Category III) , but is not a dermal irritant or a dermal sensitizer (Category IV). The tetraconazole endpoint tables and toxicological profile tables can be found in Attachment 2. 

### Conclusions: The toxicity databas e for tetraconazole is complete and adequate to support Registration Review requir e ments. The endpo int s presented in Attachment 2 are from the most recent risk assessment for tetraconazole (Memo, 14-April-2011 , A. 

### Nowotarski, el al., 

### 0380618). The hazard profi le table contain in g all newly submitted and reviewed data are pre se nted Attachment 2 as well. Based on the acceptable mitogenic mode of action for the mice li ver tumors , tetraconazole is classified as " not likely to be carcinogenic to humans at doses that do not cause increased cell proliferation in the liver· '; a non-linear approach wi ll be used for quantification of human cancer risk ( R ow land 

### et al., TXR # 0056628, Apri l 02, 2013). For future act ions, the non-cancer endpoints and safety factors for tetraconazole will need to be re-evaluated and updated based upon current policies.

Page 5 of29Tctraconazo l e Scoping Document DP# 426702


### 2.0 Re s idue C h em i s t ry Regi ste r ed Use Patterns: 

### Tetraconazo le i s reg i stered for fo li ar app li cation to soy b e an , fi e ld corn, popcorn, corn g rown for seed, s ugar b ee t , p e anut , p ec an , fruit, small, v in e climbing subgroup l 3

- 07F, a nd s ub grou p l 3

- 07G (except c ran berry). Tetraconazole e nd-u se products are registered for app li cation to these crops w ith a maximum seasona l app lic ation rate of 0.50 lb ai/acre. See A ttachment 3 fo r a summary of th e reg istered e nd-u se product s and app li cat ion sce nario s . For several crops, the field trial studies were conducted w ith o ut the addition of adjuvants and H E D required la bel re s trictions prohib iti ng th e addition of adjuvants to th e spray sol uti on. The HEO Chemis try Science Adv isory Co un c il (Che m SAC) has s in ce conc lud ed that th e use of adjuvants in field trials is unnecessary (see 

### Conclusions and Recommendations R egarding th e Requ ir e m en t for Incl usion of Adjuvan t s in Crop Field T ri a l s; l 3

- Aug

- 20 1 2)

. Therefore , lab el res tri c tion s p ro hibitin g the add iti on of adjuvants are unne cessary . In add iti o n , ChemSAC has concluded that pean ut hay i s not a signi fi cant livestock feed commodity, therefore previously required lan g ua ge prohibitin g th e fee ding of peanut ha y to li ves to c k is unn e ce ssary (see 

### Rev is ions of Feed Stuffs in Ta ble I of OPPTS 860.1000; 30 -Jun- 2008). R es idu e Ch emistr y a11d To/ era 11ce Assess111e 11t : 

### Based o n sugar beet , grape, w hea t , goa t , and poultry metabolism studi es and the confined rotational crop s tud y, H ED co nclud e d th at th e r esidues of concern are as d e fin ed in Tabl e l. HEO concluded that the t ox i co logical effects resulting fro m exposu re to T , T A, TAA , T HP , and all labile co nju gates of these com p o und s and Ml4360(C-1)-alcohol a re diff e rent from that res ultin g fro m expos ure to te traconazole; HEO concluded that the toxicity of th e rem ai nin g me tabolit es i s identic a l to that of tetraconazole. For a discussion co ncern in g these concl u sions, see 032175 l (M

. Clock -Ru st 

### e t al., 26- Jan- 2007). Provided the registered lab e ls a re co n sisten t with the labels subm itted to HEO for review and conform to any o f the revisions reque ste d by HEO , the c urrently estab li shed tolerances and th e res idu e chem istry database a re s uffi c ie nt to su pp o rt a ll reg iste red uses. Adequate me thods a re available to enforce th e c urr en tly es tabli shed plant and livestock tol eran ces (0280006, W. Donovan , I O -Jan- 2002, 0267481 , 12- 0ct-2000; 0 278236, W. D o novan, 22

- 0ct

- 200 1 ; 0 386650, T. Bl oe m , 14-Apr

-20 11 ). No additional re s idue c hemis try data are needed.
Tab le I : Re s id ues for Tol e ran ce Exp r ess io n and R i s k As s ess m e n t. 1 Matrix Residues I nc luded in Risk Assessment Residues Includ ed in Tolerance Expression She lled Pea tctraco nazo le and 1 ,2,4- lria zo le {T), tri azoly l alani ne (TA), triazolyl and Bean acetic acid ( T AA). and all labile conjugate s of these compounds Remaining Registered telraconazo l e, M 14360-alco hol (free and conjugated) , M 14360-acid, Prim ary Crops M 14 360 -DF A, M 143 60

- hyd roxydctriazolyl-0-malonyldiglucos i dc , and T, TA

. TAA and all labi le co nju aates of lh cse compo un ds tetraconazole. M 14360-alcohol (free and conjugated). M 14360-acid. Tclraconazolc Livestock M 1 4360-DFA , M 14360 (C -1 )-a l cohol (free and conjugated), M 14360-hydroxydctriazolyl-O-malonyldiglucoside , and T, TA,

T l IP, and TAA and a ll l abile coniu1.?.atcs of the se compounds tetra co na zolc, M 143 60-acid, M 14360-DFA , M 14360(C- l )

- alcohol Rotationa l Crops (free and conjugated). and TA , Tl-IP , and TAJ\ and all labile conjugates of these compounds Drinking Water tctraconazo lc not aoolicabll:



### .. 1 HED concluded that the 1ox1colo g 1cal effects resulting from exposure to I

. TA. TAA. TI IP. and all labile conjugates of the se compound s and MI 4360 (C -1 )-alcoho l are difforenl from that resulting from exposu r e 10 tc lraconazolc: HED concluded that t he toxicity of the remainin g

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metabolites is identical to that of t ctraconazolc. For a discussion concerning the se conclusions, sec 032175 1 (M. C l ock-Rust et al., 26-Jan

2007). 

### EDWCs: EFED has provided mod e led ground water (Sc reening Co ncentratio n In Ground Water (SC IGROW ); ve r. 2

. 3) and s ur face wat e r ( Pes ti c id e Root Zone Model (PRZM ver. 3.12.2 ) and Exposure Ana l ys is Modelin g System (EXAMS ve r. 2

. 98.04

. 06)) E DWCs for te traconazo l e per se 

### (0347805 , I. Maher , l-Jul- 2008). The app li cat ion scenario s w hi c h y ie ld ed th e highest acu te and chronic EDWCs are s ummarized in Table 2 and were in corporated directly into the dietar y exposure ana lys i s via th e water sources direct (a ll so urces) and indirect (a ll s ources) commoditie s . The water model s an d their description are available a t the E P A int e rnet site: http: // w,.vw.epa.gov/o pp efed l / mod e ls/wate r /

. Tab le 2: S umm ary o f Modeled Wat e r Es tim ates. Scenario Tetraconazole oer se Concentration (ug/L: oob) Peak Ye ar ly Average Minnesota

- sugar beet s aerial spray (PRZM/EXAMS) 1 6.68 4.68 Geo rgia

- oceans ae rial sorav ( PRZM/EX AM S) 2 10.45 3.48 1 EDWCs assumed 0.87 o f the basin cropped (assumes 100% of the crop treated ). 2 E DWCs assu m ed 0.85 t o account for perce nt o f bas in cropped (assumes 100% of the crop treated). 

### Co nclusions: As part o f reg istrati on re v iew , re vised E D WCs ma y be generated u s ing the curre nt modeling softw are. 

### 3.0 Dietary E xpo s ur e Die tar y Expos ur e: The mos t recent ac ute an d chro nic diet a ry ex po s ure a nal yses were c onducte d in 20 11 and co n s id ered a ll current l y reg i s t e red us es ( D 3 8 J 

### 9 l 2, T

. B loe m , 4-Apr-2011 ). The a nal y se s were conducted using DEEM-F C ID (ve r. 2.03) which inc o rp orated food co n sum pti on d ata from th e USDA CSF II (1994-1996 and 1998 ). T he unr e fined acute ana ly s is (food and water) re s ulted in exposure estimates less than H E D 's level of co ncern (S l.8 % a PAD; c hild ren 1 -2 years o ld we re the most hi g hly ex po se d p opu lati o n s ubgr o up ). Th e chronic analysi s (food an d water) was refined through the incorporatio n of empirica l process in g fac tors, average fi e ld trial res idu es , average re si du es from th e feed i ng studies, and projected percent crop treat e d es tim ates. Th e resu ltin g ex po s ure es timates are le ss th an H E D 's leve l of concern (all exposures we r e**4.9%** 

### c PAD ; all in fants < I- year o ld were th e m ost hi ghly exposed p opu la ti on s ub g roup )

. 

### Co nclusions : As part o f Reg is trati on R ev iew , a re v i se d diet ary ri s k a ssess me nt m ay be necessary to reflect potentia l rev ised EDWCs, the m os t recent d i e tary exposure mode l s, and/ or r ev i se d tox icolo g ic al PO O s. For inform ati on concerni n g exposure to th e metabolites o f conce rn th at HED ha s determin e d to be toxicolog ica ll y diff e rent from tctraconazo le , see the aggregate section. 

### 4.0 Re s i dent ia l Ex po s ure There a re no res id e ntial uses propos e d or currently r egis t e r

e d for t etraco n azo le . Therefore , residen tial handler and post

- application exposure/risk were not assessed. Spray Dri ft and Vo latili zation : Residential ex p osur es res ulting from off

- s ite tran s port (e

. g . , spray drift or vo l atili zati o n) m ay occ ur as a re s ult of app li cations of tetraco nazo le . T he Age ncy i s in the proc ess of evaluating th ese types of expos ure s and m ay, as appropriate. dev e lop po li c ie s a nd procedures to id e nti fy

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### the need for and , subsequentl y , the way to incorporate these post-application exposures into the Agency's ri sk assessments. The need for spray drift and volatilization risk assessments for tetraconazole will be exam in ed during Registration Review. Conclusions: A residential exposu re assessme nt has not been conducted for tetraconazole and therefore is not needed to suppo rt Registration Review. The need for spray drift and volatilization risk assessments for tetraconazole will be examined during Registration Review. 

### 5. 0 Aggregate Risk Assessment The most recent aggregate-risk assessment was performed in conjunction wi th the 2011 HED human health risk assessment (Memo, A. Nowotarski et al., I 4-APRIL-2011; 0380618 ). In thi s assessment it is noted that there are no resi d ent ial uses for tetraconazole; therefore, only food and water were included in aggregate assessments. Si nce the dietary exposure analys i s included the drinking wate r estimates , the discussion and exposure estimates presented represent aggregate acute , chronic, and cancer aggregate exposures. All 

### aggregate tetraconazole risk estimates a re not of concern to HED. App li cation oftetraconazole also results in exposure to T, TA , T AA, and THP. These compounds are considered to be toxicologically different from tetraconazole. H ED r ecent ly conducted an aggregate risk assessment for these compounds with the resulting exposure esti mate s less than HED's level of concern (D426493, T. Morton, 9-Apr-2015). Finally, application oftetraconazole also results in exposure to metabolites which HED has determined are toxicologically identical to propiconazole (M 14360-ketone, Ml4360

- CP(C-l)-alcohol , and Ml4360-(C-l)-alcohol). HED ha s previously concluded that the propiconazole ri sk assess m ents, which yie lded exposures less than HED 's level of concern, did not requ ire revision as the res idue est imates in corporated into these analysis were protective of the potentia l residues resulting from the application of tetraconazole. Conclusions: There is s uffici en t informati on available to assess aggregate exposure. However, new aggregate risk assessments may be required during R egistration Review to incorporate revised dietary exposure estimates and/ or toxicological PODs. 

### 6.0 Occupational Exposure Occupational handler and post-application exposures are expected based on the registered agricultural uses of tetraconazole. The registered end -us e products for tetraconazole are all emulsifiable co ncentrates (ECs) and dry flowables. The registered use sites include subgroups I 3-07F and l 3-07G (except cranberry) , field corn , popcorn , corn grown for seed and soybeans, sugar beets, peanuts and pecans (see Table A.3. 1 for details). Maximum application rates are 0.08 lb ai /Acre for foliar spray use on soybeans via ground , aerial and chemigation equipment; 0.09 lb ai/ Acre for foliar spray use on field corn, popcorn and corn grow n for seed via ground , aerial and chemigation equ ipment ; 0.10 lb ai/Acre for foliar spray use on sugar beets and peanuts via ground, aerial and chem igation equipme nt ; 0.13 lb ai / Acre for foliar spray use on pecans via ground , aerial and chemigation equipment; and 0.04 lb ai / Acre for foliar spray use on crop sub group 13-07F and 13-07 G (except cranbe rr y) via grou nd , aerial and chemigation eq uipm ent (see Table A

. 3

. 2 for details).

Page 8 of29Tetraconazole Scoping Document DP# 426702 

### Occupationa l Handlers: 

### Dermal and Inh alation: There is the potential for inJialation and dermal ex posure to occupational handlers from the currently registered use patterns of tetraconazole. In the most recent exposure as s essme nt (Memo, A. Nowotarski, I 4-APRIL-201 1 , D380618 ), all inh a lation ri sks for occupational handlers are above the target margin of exposure (MOE) of 300 with baseline protection ( i.e. , no respirator) , and a ll dermal risks for occupational handlers are above the target MOE of l 00 with baseline protection or the a ddition of g love s (required by the l abe l). Based on a rev iew of the reg is tered lab e ls for tetraconazole and previous exposure assessments for this scoping document , HED has a lre ady conducted occupational h and l e r assessments for most of the occupational handl er scenarios anticipated for the re gistered uses of tetraconazole. However , th e scenarios we re not assessed based on current ORE policies. An updated assessment wi ll be required during Regi s tration Review. Occupational Post-App li cation: 

### Dermal: H E D expec t s th a t post

- application dermal exposure will occur si nc e tetraconazole is app li ed po s t-emergence as a foliar spray. Since no post

- application data have been s ubmitted , exposures during post-application activ itie s were estimated using default assumptions for percent transferable residue and dermal transfer coefficients from H E D ' s Science Advisory Council for Exposure (ExpoSAC) Policy Number 3.1 " Agricultural Transfer Coefficients " (August 2000). At the time of the assessment, HED determined that short- and intermediate-term risk estimates are not of concern (i.e. , MOEs 2: 

### I 00) on the day of treatment ( i .e. , Day 0) for most post-application exposure activities. For high contact activities for grapes and for corn, the MO Es are 

### < I 00 on the day of treatment. The high contact activ iti es for grapes (girdling , cane tying, and cane turning) are only expected to occur for cultivation of tab le grapes. MOEs are> I 00 on day 7 after treatment. The hi gh contact activity for com (detasse ling) i s only expected to occ ur for field corn or popcorn grown for seed. MOEs are > I 00 on day 20 after treatment. Labels were revised to reflect the appropriate REis. Inhalation: There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activ iti es in previously treated fields. These potential sources include volati li zation of pesticides and re-suspension of dusts and/ or particulates that contain pesticides. The ag e ncy s ought expert advice and input on issues related to volatili zation of pesticides from i ts Federal Insecticide, Fun g icid e , and Rodenticide Act ( FIFRA ) Scientific Advisory P ane l (SAP) in December 2009 , and received the SAP ' s final report on March 2 , 20 I 0 (http: // www.epa.gov/ scipo ly/ SA P/ meetings/ 2009/ 120 I 09meetin!!.html). Th e agency has evaluated the SAP report and has developed a Volatilization Screening Too l and a subsequent Volatilization Screening Analy s i s (http: // www .r egulations.gov/# !docketDetail:D = EPA- HQ-OPP- 2014 -0 219)

. During Registration Review , the agency wi ll utili ze this analysis to determine if data (i.e. , flu x stud ie s , routesp e cific inhalation toxicological studies) or further analysis is re quired for tetraconazole. In addit ion , the Agency is continuing to evaluate the ava ilabl e post-application inhalati o n exposure data generated by the Agricultural Re entry Task Force. Given these two efforts, the Agency will continue to

Page 9 of29Tetraconazole Scoping Document DP# 426702


### id e ntify the nee d for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments. 

## Conclusions: The occupationa l exposure database i s adequate to support the Registration Review process for tetraconaz ole. Th e most re cen t occupational handler did not identify ri sks of concern, but are not reflective of current exposure policies and data. For occupationa l post-application, MOEs of concern were observed. Based on a review of previous assessments and current registered labels, HED has already conducted occupational assessments for most of the occupational handler and postapplication scenarios anticipated for the registered uses of tetraconazole. However , durin g Re gistration Review, updated occupational assessments wi ll be conducted to reflect all currently registered uses, using current ORE policie s and/ or updated toxicolog ical POOs as needed

. 

### DFR: In accordance with 40 CFR 158 , DFR data are req uired for occupational (e

. g. , crop, nursery , and g reenhouse use sites) or residential (e

. g., ornamental and vegetable gardens, pick your own farms and retail tree farms) uses that could r esu lt in post-application exposure to foliage. In the absence of chemical

- specific DFR data , EPA uses default va lu es. Based on a review of the registered uses and maximum app li cation rates , the high est estimated occupational post-application expos ure usin g d efault DFR values for tetraconazole is not minimal in co mp arison to th e level of concern ( i. e . , the calculated MOE is not greater than 2 times higher than the level of concern for com, grapes, sugar beets and peanuts (MO Es range from 23 to 160 compared to the LOC of 100). Therefore, HEO is recommending that D FR data be required to facilitate any necessary exposure assessments refinements. This recommendation was also noted in a response to a DFR data waive r request ( D4 265 l 1 ). 

### 7 .0 P ubli c Health and Pesticid e Epi demiology Data The Agricultura l Health Survey (Al-IS) is a high quality , prospective ep idemiolog y study evaluating the link between pesticide use and various health outcomes including cancer. The AHS includes private and commercial pesticide applicato rs and their spouses. If there are AHS findings relevant to a particular pesticide go in g through registration review , the Agency w ill ensure they a re considered in the problem formulation/ scopi ng phase of the proce ss and, if appropriate , fully reviewed in the risk assessment pha s e of the process. The AHS includes information o n use of 80 different pesticide active ingred ients commonly used in agriculture. Tetracona zo le is not included in the AHS, and therefore this study does not provide informati o n for this report. The Sentine l Even t Notification System for Occupational Ri sk (SENSOR)-Pesticides database covers 12 s tate s from 1998-2011, although reporting varies from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources , including: reports from loc a l Poi so n Control Centers , state Department of Labor workers' compensation claims when reported by physician s, reports from State Departments of Agriculture, and physician reports to state Departments of Health. Although both occupational and non-occupational incidents are included in the database , SENSOR-P esticides focuses on occupat ion a l pesticide incid ents , and is of particular value in providing that in fo rm at ion. The state coordinator at each of the 12 respective state Departments of H ealth conducts case follow -up activities such as obtai nin g medical records to verify symptoms and severity. Using standardi zed protocol and

Page 10of29Terraconazole Scoping Documen t DP# 426702



### case definitions d e riv ed from poi so n center reporting, th e s tate SENSO R-P estic ide coordinator enters th e incident informati on into the state-ba sed system w hi c h is se nt to N IO S H annually to be aggregated. A review of SENSO R-Pesticides 1998-20 l 1 id e n tifies two cases, stemming from one eve nt , involving tetraconazole. The two cases involve multipl e active in gred ie nts. These two cases occu rred in No r th Caro lina i n 2010. Both cases were low in severity. The cases were res id ent ial bystanders in th ei r home. A certified applicator was making an aer ial app li cati o n to soybean s in a nearb y fie l d and the product drifted to their home; as they were walk in g outside of the hom e " the mist hit them as they we re running out of the way . " They both ex peri e nc e d co u gh/choke and one also had gastro intestina l symptoms. Products used in this aerial ap plication i nclude H eadline Fungi cide, Demark 230 ME Fun gicide and Declare. The applicator did receive c it ations fo r v iolating F lFRA , in c ludin g " u se not in acco rd ance w ith label , operat ing unl ice n sed equ ipm e nt , the department of pesticides was i n a no deposit zone, and depositing in a harmful mann er." 

### 8

. 0 Human Incident Data: OPP IDS (2012) O PP 's Incid e nt Data System ( ID S) includ es reports of all eged hum a n he a lth in c ide n ts from various so urce s, includin g mandatory FIFRA Section 6(a)(2) reports from registra nt s, other federal and s tate health a nd e nvironmenta l agencies , and in d i v idu al co n sumers . IDS records incid ents in o ne of two m od ul es: Main ID S a nd Agg regate ID S :

o Ma in ID S contain s in c id ents resu lt ing in higher seve rit y ou t comes and provides more detail with regard to case specifics. Thi s sys t e m stores incident data for death , major and m odera t e incidents , a nd it includes in formatio n a bout the locat ion, date , and natur e of th e in cident. Main ID S incidents in vo l vi ng o nly one active ingredie n t (as opposed to pe s ticid e products with mult ip le active in g red i ents) a re cons id ered t o prov id e more certain information abo ut the potential effects of exposure from the pesticide.

o Aggregate ID S contains in c id en t s resulting in le ss severe human incidents (minor , unknown , or n o effects o ut comes). These are reported by reg i s tr ants on l y as counts in what are aggregate summar ies. For the Main ID S, from Janu ary I , 20 l 0 to February 4 , 20 15 , there were no incidents reported invo lving t etraconazo le. I n Aggregate IDS , from January I , 20 I 0 to February 4 , 20 15 , t here were three incidents reported involving tetraconazol e . Th ese incidents were classified as min o r seve rity. Ov erall , there are few incidents reported to IDS in volv in g tetracona zo le. 

### Co nclusions: B ased on th e low fr eq ue ncy and severity of inc ide nt cases r eported for tetraco nazol e in both IDS and SENSOR-Pesticides, there does not appear to be a concern at this tim e that would warrant fu r ther in ves ti gation. T he Age ncy w ill cont inue to monitor the incident i nformation and if a concern is triggered, additional analysis w ill be included in the risk assessment.

Page 11 of29Tetraconazole Scoping Document DP # 42670 2


### 9 .0 To le r a nc e Assess m e nt and In te rn ation a l H a rm o n iz ation Attac hm en t 4 is a su mm ary of the Canad ian , Mexican , and Codex maximum residue limit s ( MRL s) for residues of tetracon azo l e . T he re are no Codex or Mexican MRL s es tablished for residues of te traco nazo le. T h e Canad ian an d U .S. tetraconazole tolerance expressions are id e ntic a l as are the to ler ance va lues for the common crop comm o diti es. Howev e r , th e l ive s tock tolerance values are not harmoniz ed. As part of r eg i strat ion re v iew, H E D w ill reevaluate the Canad ian , Mexican , and Codex MRLs and h a rmoni ze w he n p ossib le. 

### 10

. 0 E n v iro nm e nt a l Ju s tic e Potential areas of env ironmental ju st ic e concerns, to the extent possible , were con si d e r e d in th e mo s t recen t tetracon azo le hum a n-h ea lt h risk assessment, in acco rdance with U.S. Exec utiv e Order 1 289 8 , " Federal Ac tion s to Address Environmental Justice in Minority Populatio n s and Low-Income Popul atio n s '. " The OPP typi ca ll y considers the hi g he s t potentia l exposures from the legal use of a pesticide when conducting human -hea lth ri sk assess m en t s, includin g, but not limited to , people who obtai n drinking water from sources near ag ri c ultur a l area s, the variability of diet s within th e U.S. , and p eo pl e who may be exposed when harv es tin g crops. Should the se highest ex po sures indicate p ote nti al risks of concern, OPP further refines the risk assess m e nts to e n s ure that the risk est imates are ba se d on the b est avai l ab le i nformat ion. 

### 11.0 C umul a ti v e Te traco n azo le is a m e mb e r of the triazole-contain i ng class of pesticide s . A l thou g h conazol es act s imilarl y in pl a nts (fungi) b y inhibitin g e rgos t e rol biosynthesis , there is not necessar il y a relation s hip between their pesticidal acti vi ty and th ei r m ec hani s m of toxicity in mammal s . Structural similarities do not co n s titute a common mecha n i s m of toxicit y . Ev idence i s need e d to es t abl i s h that the chemicals operate by the same , o r ess enti all y the same , seque nce of m ajo r bi oc he mic a l events (E PA , 20 0 2). In conazoles , howev e r, a variable pattern of toxicolo g ical responses is found; so m e are hepato toxi c and hepatocarcinogenic in mic e. So m e induce thyroid tum ors in rats. Some induc e developmental , reproductive, and neuro logical effects in rod e nts. Furt he rmo re, the conazo les produc e a diver se ran ge of biochemical eve nt s including alte red cholesterol levels, stress re sponses, and a ltered DNA methylation. 

### It is not clearly understood w het h e r th ese bi oc hemical eve nt s are directly connected to their toxicological o utcomes
. Thus , ther e is currently no evidence to indicate that co n azo lc s s h are common mechanisms of tox icity a nd EPA is no t fo ll ow in g a cumulative ri s k approach ba se d on a common me c hani s m of toxi c ity for th e conazoles. For informati o n regard in g EPA's procedures for cumu lating effects from substances fo und to have a co mm o n mechanism of toxicity , see EPA ' s we b s ite at http: //www

. epa.gov/pest icides/cumulative. 

### 12

. 0 Hum a n S tudi es Pa s t tetraconazole risk assessme nt s r e ly in part on data from s tudi es in which adult human s ubj ec ts were intentionally exposed to a pe st icid e to determine their dermal and inhalation e xp os ur e. Many such stu di es , involving exposu re t o many diff e rent p es ti ci d es , comprise ge neric pesticide ex po su r e d a taba ses

1 htt p ://www . epa. g ov/compliance / environmentaljustice / resource s/policy/e xec

_ order

_ 12898

. pdf

Page 12 of29Tetraconazole Scoping Document DP# 426702



### suc h as the Pesticide Handlers Exposure D atabase (P HED ) , the Outd oor Re s idential Expos ure Task Force (ORETF) Databas e , the AHETF Datab ase, and th e A RTF D a ta ba se. EPA has reviewed a ll the studies supporting these multi-pesticide g en e ric exposure databases, and ha s found no c lear and convincing evi d ence that the conduct of any of them was eit her fundan1entally unethica l or significantly deficient rel at iv e to the ethica l standards prevailing at th e tim e the research wa s co nducted . A ll applicab le requirements of EPA ' s Rule for the Protection of Human Subjects of Research (40 CF R Part 26) ha ve be e n satisfied , and th ere is no reg ulatory b arri er to continued reliance on th ese stud ies. 

### 13.0 Data Requi r ements Required Under Registration Review Th e following data deficiencies were identified for tetraconazole:

• Tox ico lo gy: None • Residue C hemistry: Provided the registered labe l s a re cons iste nt with the lab e ls s ubmitted to H ED for review and conform to any of the revisions requested by H E D , no additional residue chem i stry data are required. • A DFR study is required (OCS PP Guideline # 

### 875.2100). In a dd iti on , EPA ant ici p ates co ndu ctin g the following ri s k assessment updates durin g Regi s tration Review:

• Toxico logy: Reevaluate toxicity endpoint/dose selection, along with the FQPA SF ba se d o n curre nt HED poli cy . • Dietary Expos ure : A rev ised d i e tar y exposure anal ys is ma y be req uire d to refl ect th e m ost recent d ietary exposu re models , potential revised EDWCs , and/ or changes to the toxicological POD s. • The nee d for s pray drif t and vo l at ili zat ion ri s k assessments fo r tetraconazole wi ll be examined during R eg i strati o n Re view. • Agg regate Exposure: R evised aggregate exposure analyses m ay be required to refl ect revised dietary expos ure est im ate s and/ or changes to the tox ic o logi cal POD s. 

### 14.0 R efere nce s Table 3: Memoranda R e levant to Regi s trati o n Re v iew. Author DP# B arcodc / Date Title TXR # HE D

- Ri sk Asse ss ment Document s M. C l ock -Ru st Petiti o n Nos: 5F697 I. 6F7 0 84

. 6F 6023. 9 F5066; Tetrncona zo le : I lumane t a l

. D321751 26- Jan- 2007 H ealth Ri sk A ss es sment for Prop os ed Us es on Soy be a n, Su g ar Beet. Pe a nut. Peca n. and Turf. P

etition No s: 435873. 4363 3 3 ; T ctraco n azo l e: Hu man-Health Ri s k A.Nowa ta r s ki D38 06 18 14- April-2 0 11 Asse ss m e nt for Propose d Uses on S m all Fruit Vine C limbin g Sub g r o up 13- 07F. Low-Growin.Q Berry Sub_g r oup I 2

-07G , and Fie l d Corn and Popcorn

. HED- Tox icolo 2v Doc um ent s

J

. R o wland TXR #0056628 02

-April -1 3 Tctracona zole: Report of the Ca n cer A ss es sment R eview Committee HED

- R es idu e Ch e mi stry D ocuments W

. Donovan D259205 8-May-2000 PP # 7E04830. Tetraconazo le u se on Bananas. Eva lu a tion of Res idu e Data and Anal ytical Methods. MRlD # s 442681-06 thru -11.

Pa g e 13 of29Tetraconazo le Scopi ng Document DP # 426702

Tab le 3: Memo r a n da R e leva n t to Regi s tra ti o n R ev i ew. Au th or DP# Barcode / Date Title TX R # PP# 9F06023. Tetraconazole use on Peanut s. Evaluat ion of Re s idue W

. D ono va n D259321 I8-Ma y-2000 Da t a and Ana l ytica l M ethods. MRJD #s 448654-03, 448654-07 , and 449005-01. PP# 9F05066. Tetraconazo le use on Sugar Beet s. Evaluation of W

. Donovan D2544 1I I8-May-2000 R esi du e Data and Ana lyt ical Method s. MRID #s 44 7513 -1 1 thru -18 , 450684-04 , and 450684-05. PP# 9F05066. Tetraconazole: Additional Data to Amend 1-IED 's W. Donovan D267481 I2-0ct-2000 R e s idu e Data and Analytical Methods Memoranda Concern in g Sugar Beets , Bananas , and Peanuts. PP#s 9F05066, 9F06023, and 7E04830. Tetraconazole

. Additional W

. Donovan D278236 22-0ct-2001 Data to Amend HED's Residue Data and Ana lytical Methods Concerni n g Sugar Beet s, Banana s, and Peanuts (D26748 l , W. Donovan, 12-0CT-2000 Co rre spo nd ence to Mark Wirtz, Chemis t Food and Drug W. Donovan 02800 0 6 IO-Jan-2002 Admini s tration Division of Pesticide s and Indu s trial C hemical s r egard in g analytical methodology for residues oftetraconazole. PP#s 7E04830, 9F05066, and 9F06023. Tetraconazol e in/on \V

. Donovan D280005 IO-Jan-2002 Banana s, Sugar Bee ts , and Peanuts. R es ult s of P e tition Method Validation (PMY). PP#s 9F05066 , 9F06023 , and 7E04830. Tetraconazole. Amendment s d 19-NOY-2001 , 27-DEC-200 1 , 08-FEB-2002, and W

. Donovan D282558 I7 -M ay-2002 09-APR-2002. Additional Data to Amend HED' s Re sid ue Data and Analytical Meth ods Concerning S ugar Beets, Bananas , and Peanut s (D278236, W. Donovan, 22-0CT-2001). T. Bloem D310 763 24

-Nov -2 004 !Reg istration 9F5066

. R es idue Chem is try Summary for App li cation K>f Tetraconazole to Sugarbeet. T. Oloem 0332 139 1 4-Sep-2006 Multire s idue Method (MRM) te s t information for tetraconazol e sent to the FDA Tetraconazole. R esidue Chemistry Summary for Ap plication of Te traconazole to Peanut and Sugar B eet. Petitioner 's Response to De fici enc ie s Identified in t he Following Memoranda: D25 932 l T. Bloem D327489 23-Jan-2007 (peanu t

- , W. Donovan , 18-May-2000); D2544 1 l (suga r b ee t

- W. Donovan , 18-May-2000); D26748 l (W. Dono va n , 12-0ct-2000); D27 82 36 (W

. Donovan, 22-0ct-200 I) ; D 282558 (W. Donovan , 17- M

ay -2002); and D310763 ( T. Bloem , 24

-Nov-2004)

. T. Bloem 033 1594 23 -Jan- 2007 Tetraconazo le. Re si du e Chem istry Summary for Application of Tetraconazole to P eca n . T

. Bl oem 0329 379 23-Jan-2007 Te trac onazole. Section 3 R egist ration for Application to Soybeans. Sum m ary of Analytical Chemistry and R es idu e Data. Tetraconazole. R esi du e Chemistry Data for Application of Tetraconazo le t o Peanut and Sugar Beet. Petitioner's Respons e to D

e ficiencies Ident ified in the Followin g Memoranda : D25932 l T. Bloem 0342523 22-Aug-2007 (peanu t

- , W. Don ovan, 1 8-May-2000) ; D 2544 I I (sugar beet

- W. Donov a n, 18-May-2000); D267481 (W. Donovan , 12-0ct-2000); D27 82 36 (W. Dono van, 22-0ct-200 I); D282558 (W. Dono van, 17- May -2002); D3 l 0763 (T. Bloem , 24-Nov-2004); and D327489 (T. Bloem , 23

- Jan-2007). Tetraconazo l e. Specia l Lo cal Needs (SLN) Section 24(c) R

eg istration to R ed uc e the Plantback Inter val (PB I ) for Sugarcane T. Bloem 034855 1 8-Apr-2008 Following Application ofTetraconazo le to Soybean and Label Amendment to Reduce th e PBI for S ugarcane and Wheat Followi n g Aoolication o f Tetraconazole to Soybean .

Page 1 4 of29Tetracon azole S coping Docum e nt DP# 426702

Table 3: Mem ora nda Relevant to R el!is tration Re view. Au th or DP# Barcode / Date Title TXR # Tetraconazole. Review of Information Submitted by the Petitioner T. Bloem 0349705 4-/\pr-2008 ( 8-June-2007) in Respon se to Re s idue Chemistry Deficiencies I dentified in 0329379 (T. Bloem , 23 -Jan -200 7). D ecis ion No s.: 381428 and 389483. 40 C FR 180.557

. T. Bloem 0353020 26-Jun-2008 Tetraconazole. Residue C hemistry Summary for Application of Tetraconazo le to Grape. Tetraconazole. Review of Grape Fruit Storage Stability Data T. Bloem 0384213 I3-Jan-2011 Submitted in R esponse to Residue Chemistry Deficiencies I dent ifi ed in 0353020 (T. Bloem, 26-Jun-2008). T

. Oloem 0386650 14-Apr-2011 Tetraconazole

- Enfo rc ement method to FD A Tetraconazole

. Residue Chemistry Summary for Application of T

. 131oem 0382300 I4-Apr-201 1 Tetraconazole to Field Co rn , Pop co rn , Small Fruit Vine Climbing ( Except Fuzzy Kiwifruit) Subgroup I 3-07F , and Low-growing Berry Subgroup I3-07G (except cranberry). Tetraconazole in / on Fi e ld Com, Popcorn , Sma ll Fruit Vine C limbin g ( Except Fuzzy Kiwifruit) Subgroup I 3-07F , a nd Low-growin g Berry T. Bloem 0399658 12-D ec -2 0 12 S ubgroup 13-07G (except c r anberry). R eview of Storage Stability Data Submitted in Respon se to Re s idue Chemis try Deficiencies I dentified in 0382300 (T. Bloem , 14-Apr- 201 1 ). T. Bloem 0416020 l 2-Mar-2014 Tetraconazole in /o n Sugar Beet s ( la bel amendmen t). Summary of Analytica l Chemistry and Residue Data. HED

- Occ uoational-Re s idential Ex 1 >osure Documents K. Lowe 0426511 21-May- 2015 Tetraconazole. R eview of lsagro USA 's Di s lodgeable Foliar Residue (DFR) S tud y Waiver R eq ue s t. HED

- Hum a n Incident Data S. Recore 0427419 2 l-M ay-20 15 Tetracona:zole: Tie r I R eview of H uman In c idents for the Scoping Document 

### 15.0 Attachments Attachment I: 

### T e traco na zo le and Its Metabolites C hemi cal I dentity Table. Attachment 2: T etraco na zo l e Endpoint Se l ection and Toxicolog ical Profil e Tab l es Attachment 

### 3: R egis tered End

- Use Produ cts and Application Scenarios/ Rates (information provided by BEAD ) Attachment 4: IRL Sheet

cc: A. Dunbar(RABI), T. Bl oem ( RABI ), J. Miller ( RABI ) ROI : RABI ( I l-MAY- 20 15 ), G. Krarner(I 1-MAY-201 5), T. Morton (I I-MAY-2015) A. Dunbar:S I0952:PY-S:(703 ) 603-06 I I : 7509P:RAB I

Pa ge 15 of29

### Tet r aconazo l e Scop in g D oc um e nt DP# 426702


### Attachment 1: T e tracona zo l e a nd Its Metabolites Chemica l Identi ty Table.
Tab l e A .1.1 : Test Com o und No me n c lature .

Chemica l Structure Cl

Common name Co m an ex crimental name IUPA C name CAS name CAS#
Table A. 1.2 : Ph ys i coche mi ca l Properti es of th e Tec hni cal Grade Tetra co n azo le. Meltina ooint/ranl!e Not aoolicable

- te st is a viscous liquid pH 5.48 in DI I hO 5.47 for satu rated solu tion at 20 ° C MRID 44268 1 04: D259842. Density 1 .43 82 g/ ml a t 20 ° C B. Kitchens. I l-Apr-2000

. 1.42 52 g/ ml at 30°C Wate r solubi lit y (PAI >94. 16%) 159.31 m l!./L at 25 ° C So lvent so lubility Readil y in dichloromethane. acetone. and EPA fact sheet methano l 0.13 x 1 0 2 Pa at 35.5°C MRID 44305301: D259842 , Vapor pressure (PAJ >99.65%) 0.5 8 x 102 Pa at 46.5 ° C B

. Kitchens. I l-Apr-20 00. 2.985 x I0 2 Pa at 60 ° C Dissociation constant (Ka) 0. 158

- 0.3 1 6 MR l D 46055603; D294 I 98, B. Kitchens. 26-Jan

- 2004. Oc t ano l /water partition coeffic ient ( P AI > 99 .65%) log P ow = 3.53 at 25 ° C MRI D 4430530 I: D259842. B. K itchc ns, 1 l- Ap r- 2000. UV / visible absorotion spectrum not available



### Page 16of29Tetraconazole Scoping D ocument DP# 426702


### Attac hment 2: Tetraconazo l e End point Se l ection and Toxicity Profile Tab l es for Tetraconazolc Technical. Tab l e A.2.1. S umm ary of Toxico l og ica l Do ses and End p oint s for T et racona zo le for Use in Di etary and NonOccupationa l Hum a n Healt h Risk Asse ss ment s. Expos ure / Uncertainty/ FQPA RfD , PAD , Scenario POD Safety Factors LOC for Ri sk Study a nd Toxicological Effects Assessment /\cute Dietary NOAE L = 50 UF A

= IOX aRfD = 0.5 Acute neurotoxicity (rat) General mg/kg/day UF11 = !OX mg/k g/da y LOAEL = 200 m g/

k

g/d ay du e to Population S F FQP A= I X aPA O = 0.5 decreased motor act ivity o n day 0 m

g/kg/day in both se xes , a nd clini ca l signs in females including hun che d posture , d ecreased defecation, and/or r ed or ye llow materia l o n various body s urfaces. Acute Dietary NOAEL = UF A = IOX a RfD = 0 .225 D eve lopm e ntal to xicit y s tud y (rat) Females 13-49 22.5 UF11 = !OX mg/kg/da y D eve lopmental LO AEL = I00 years of age mg/kg/day SFFQPA = IX aPA D = 0.225 mg/kg/day based on in creased mg/kg/day in cide nce of small fetuses , supe rnum erary ribs, and hy droure ter and hydro nep hr os is. Ch ronic Dietary NOA EL = U F A

= IO X cR fD = 0.0073 Chronic oral toxicity (dog) (A ll 0.73 UF11 = IOX mg/kg/day LOAEL = 2.95/ 3.33 (M /F) Populations) mg/kg/day SFFQPA = IX cPA D = 0.0073 mg/ kg/day , b ased on absol ut e and mg/kg/day rel ati ve kidney weigh ts and hi s top ath o logi cal changes in the male kidn ey. Cance r (o ral , C lassi fi cation : " Likel y to be Carcinogen i c to Hum a n s . " Q 1 • = 2.3 x I0· 2 (mg/kg/day)' 1 based dermal , inhalat io n) on male mouse liver benign and/or malignant co mbin ed tumor rates. Point of departure (POD)= A data point or an estimated poi nt that is derived from obser ved dose-r esponse data and used to mark the beginni ng of ext rap olation t o determine ri s k associated with lowe r e nv ironm e ntall y re l e vant human expos ur es. N OAEL = no-obse rv ed adverse -eff ec t level. LO AE L = l owes t-observed adverse-effect level. UF = uncerta i nty factor. UF A= ex trapolation from a ni mal to human (in te r species). UF11 = potential variat i on in sens iti vi t y a mo ng me mb ers of th e human popul a ti o n (intraspec ies)

. UF L= use of a LOA EL to extrapo late a NOA EL. UFs = use of a short-rerm stu d y for long-term ri sk assessment. UF oo = to account for th e absence of key date (i.e., lack ofa c riti ca l study)

. FQPA SF = FQ PA Safe ty Factor. PAO = popul at ion-adjusted d ose (a = acut e, c
= c hroni c). RfD = reference dose. MO E = margin of expos ure. LO C = level of concern. NIA = not applicable. Table A2.2. S ummary of Toxicolo g i cal Do ses a nd Endpo int s Tetracon azo le for Use in Oc c upati o nal Human H ea lth Ri sk Ass es s ment s. Exposure/ POD Uncertainty LOC for Ri s k S tud y and T oxicological Effects Scenario Facrors Assess ment S hort -T erm ( 1- Oral study UFA = IOX LOC = 100 Reproductive toxicity

- rat 30 days) Dermal Parental NOA EL UF11 = !OX (occupational) Parental LOAEL = 4.91 5.9 = 0.7 mg/k g/d ay mg/kg/day ( M / F) , based on (dermal- increa se d mortality of adul t abso rpti o n rate = f e mal es in th e P and F 1 12 % 1) generations.

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Tabl e A2.2. S umm ary o f To x icol og ica l Do s e s a nd Endpoints Tetracona zo l e for Use in Occupati o na l Human H ealt h Ri sk Assess ment s . Expo s ure/ POD Uncertainty LOC for Risk Study and Toxicological Effects Scenario Factors Assessment lnt ermed iate- Oral study UFA= IOX LOC = 100 Chronic oral toxic it y - do g Tenn ( 1-6 NOAE L = 0.73 UFH = IOX (occ upational ) LOAEL = 2.95 / 3.33 (M/F) months) Dermal mg/kg/day mg/kg/day, based on absolute (dermal- and relative kidney weights and absorp ti on rate = hi sto pathological changes in the 12 % 1) male kidney. Short ( 1- 30 Occupational 1.3 UFA = 3X LOC = 300 28-Day I nhalation toxic it y- rat days) and mg/kg/day; HEC UFH = lOX (occupa tional ) LOAEL = 1.3 mg/k g/ day Interm ediate- = 0.0048 mg/L; UFL = lOX (0.0048 mg/kg/L, 0.0548 m g/L tenn ( 1-6 4.84 mg/m 3 ; (rat)) for males and females , months) 0.0548 mg/L (rat) ba se d on s quamous ce ll Inhalation metaplasia of laryngeal mucous , mononuclear cell in filtration, goblet hyperplasia and hypertrophy of nasal cavity and nasopharyngeal duct and follicular hypertrophy of thyroid in males. *NOAEL not established. Cancer (oral, Classification: " Likel y t o be Carc in oge nic to Hum a ns." 

### Q1 ' = 2.3 x 10

- 2 (mg/kg/dayy' based dermal, inhalation) on male mouse liver benign and/or mali g nant combi ned tumor rates. Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapo lati on to determine ri sk associated with lower e nvironmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse -e ffect level. UF = uncertainty factor. UFA = extrapolation from anima l to human (in terspecies). UFH = po tential variation in sensitivity among members of the human population (intraspecies). UF1. =use ofa LOAEL to extrapolate a NOAEL. UFs =use ofa short- term study for lon g- t erm risk assessment. UFoe = to account for the absence of key date ( i .e., lack ofa critical study). MOE = margin of exposure. LOC = level of concern. N IA = not applicable. 1 12% dennal-absorption factor

- Derived from HIARC report TXR NO. 0052657

.

Tab le A .2.3. Acute T o xicit y Pr o file

- Test S ubstance. Guid e line No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute o ra l 44268 11 2 LDso = 1 031 111 mg/kg 870.1200 Acute dermal 44335501 LD so 

### > 2000 111 mg/kg 870.1300 Acute inh alation 44305302 LCso 

### > 3

. 66 mg/L IV 870.2400 Acute eye irritation 44335502 Sl i gh t eye irritant 11 1 870.2500 Acute derma l irritation 44335503 Not a dermal IV irritant 870.2600 Skin se ns itization 44268 11 3 Not a dem1al NA sens iti zer

Page 1 8 of29Terraconazole Scoping Document DP# 426702

T able A.2.4. S ubchr o ni c, C hronic , a n d Ot h e r Tox i city Profile.

Guideline Study Type MRJD No. (year)/ R es ult s No

. C las sificatio n/D oses 8 70.3 100 28-Day oral 44751304 ( 1988) NOAEL was not established. toxicity (ra t ) Acceptable/ non-guid e line LOA EL = 70 m g/kg/day , based on dec reased 0, 70,200,or500 body wei g ht ga in s in and increased liver mg/kg/day via ga vage weights bo th sexes, and increased kidne y weight s in mal es and ovary wei g ht s in fema les. 870.3 100 28 -D ay o ra l 44751305 (1988) NOAEL = not establ is hed ( M), 3.8 (F) toxi c ity (ra t ) Acceptable/ nongu idel ine mg/kg/day. 0, 40, 160 , 640, 2500 o r LOAEL = 4.4 / 15.3 (M/17) mg/kg/day, ba se d on 10000 ppm increa se d liver we ig ht s. e nlarged li vers and M : 0, 4.4, 17.5 , 68.4 , 229 enla r ged cenrrilobular hepataocyt es. mg/kg/day; F: 0, 3.8 , 16

. 1 , 62

. 3 , 2 17 mg/ kg/da y 870.3100 2 8-Day o ral 44751306 ( 1989) NOAE L = 4.19 mg/k g/ day ( M)

. toxi c ity (ra t) Acceptab le / nonguid e line LOA EL was not established. 0 , 2, 5 , 15, or 40 ppm M: 0, 0.21, 0.52, 1.57, or 4. 1 9 mg/k J:?/day 870 .3 100 90-Day ora l 44335504 ( 1988) NOA EL = 4.1 1 5.5 mg/ kg/day (M / F). to xic ity ( rat ) Acceptable/ gu idelin e LOAEL = 23.9 /28.7 ( M /F) mg/k g/ d ay, wa s 0 , I0, 60, or 360 ppm based upon increased body weight gai ns in M: 0 , 0.7 , 4.l , or23.9 males , d ecreased body weight gains in females , mg/ k

g/day increased abso lut e and li ve r we i g ht s in both F: 0 , 0.9, 5.5, or 28.7 sexes, enlarged livers in males, en larged mg/ k

g/da y cen tril obular hep atocyte s in male s and females. 870.3100 90

- Day oral 44778701 ( 1989 ) NOA EL = 4 m g/kg/da y (M/F). to xicity (m ic e) Acceptable/ non- gu id e line LOAEL = 16 / 20 mg/kg/day, based on s in g le 0 , 5, 25, 1 25, or 625 ppm liver cell degeneration in males , and increa se d M : 0 , 1 , 4, 16 , or 85 sc rum g lut amic py ruvic tran s amina se (SGPT) mg/kg/day and serum g lu tamic oxaloacetic tran sam ina se F: 0 , I , 4 , 20, or 103 (SGOT), decrea se d BUN levels , increased mg/kg/da y abso lut e and re la tive li ver weigh ts and presence hepatoce llular s in g le cell nec ro sis in femal es . 870. 3 150 90-Day ora l NA 1 NA toxicity ( dog) 870.3200 2 1-Day dennal 44751307 (1992) System ic Toxici ty toxicity (s pe c ies) Acceptable/g uide line NOAEL = 241 (a i) mg ai/ k g/d ay. 0 ,2 50 , 100 ,o r2000 LOAEL was not established. (form ul ation) mg/kg/day Dermal Toxicity Actual ai 0 , 30. 1 , 1 2 0.4 , NOAEL = not es tablished

. or 24 1 mg/kg/day LOA EL = 30 (a i) mg/k g/day, ba sed on dermal irritation. 870. 3465 90 -D ay inhalation 46990301 (2006) NOA EL = not es tablis hed. toxicit y (ra t ) Acceptable/ no n-guid e line LOAEL = 0.0548 m g/L ( 14.3 mg/kg/day) for 0, 0.0548, 0. 1 59, or 0.520 males and female s, based on squamous cell mg/L metapla s ia of laryngeal mucosa , mononucl ear (0, 14.3,43.15,or 141.15 cell infiltra ti on , gob let hype rpl as ia a nd mg/kg/ day) hypertrop hy of nasa l cavi t y and na s opharyngeal duct a nd fo ll icular hypertrophy of thyroid in males.

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Table A

. 2.4. S ub c hr o ni c, C hr on ic , a nd Other Toxicity Profil e.

Guideline Study Type MRID No. (year)/ Re s ult s No. Classification/Doses 870.3700a Prenatal 44335505 (1990) Maternal NOA EL = 22.5 mg/ kg/day

. developmental in Acceptable/g uideline L OA EL = 100 mg/kg/day , based on decreased (rat) F: 0, 5, 22.5, or I00 bod y weight gain, and food consumption and mg/kg/day (G D 2-15) increased water int ake, and increased liver and kidney weights. Developmental NOAEL = 22.5 mg/ kg/da y. LOA EL= I00 mg/kg/day, based on inc reased incidence of small fetuses , supranumerary ribs and hydroureter and hvdroneohrosis. 870.3700b Prenatal 44335506 ( 1990) Materna l NOAEL = 15 mg/kg/day. d eve lopmental in Acceptable / guideline LOA EL= 30 mg/k g/ day , ba se d upon decrea sed (rabbit) F: 0 , 7.5, 15, or 30 body weight gain

. Developmenta l NOAEL = m

g/kg/ day 30 mg/ kg/day

. LOAEL wa s not es tablished. 870.3800 Reproduction and 44305306 ( 1991) Parental / Systemic NOAEL 

## = 0.7/ 0.8 mg/k g/day f e rtility effects Acceptable/ guideline (M/ F). (rat) 0 , I 0, 70, and 490 ppm Parental LOAEL 

## = 4.9 1 5.9 mg/k g/day (M/F) , M : 0 , 0.7 , 4.9, and 35.5 based on in creased mortality of adu lt fema les in mg/kg/da y the P and F 1 generations. F: 0, 0

. 8, 5.9, and 40.6 R ep roduc tiv e NOA EL = 35.5 /40.6 mg/ k

g/day mg/k g/day (M/ F). LOAEL = Not established

. Offsp r ing NOAEL 

## =4.91 5.9 mg/k g/day. LOAEL = 35.5 /40.6 m g/

k

g/day (M/F), ba se d on decreased litter weight and mean pup weight in litt ers of all generat ions before weaning and increa se d relative live r wei g hts at weaning in both sexes of all litt ers. 870.4 lOOb Chronic toxicity 44305303 ( 1990) NOA EL= 0.73 /0.82 (M/F) mg/k g/da y. (dog) Acceptable / guideline LOAEL = 2.95 / 3.33 (M/F), based upon M & F: 0 , 22.5, 90 , or 360 increa se d abso l ute and relative kidney weights ppm . and histopathological chan ges in th e male M: 0, 0.73 , 2.95, or 12. 97 kidney

. mg/kg/day At th e high dose of 12.97 m g/kg/day, liver F: 0, 0.82, 3.3 3 , or 14.5 effect s were observed incl uding increased mg/kg/day serum levels of alkaline phosphata se, y glutamyltransferase , alanine aminotransfera se and ornithine carbamoyl tran s ferase in both sexes from s tudy week 13 to 52, increased absolute a nd relativ e liver and kidne y wei g hts for both sexes, and hi s topathologic a l chan ges in both orga ns.

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Ta bl e A.2. 4

. S ub c hroni c , C hro ni c, a nd Oth e r Tox ic i ty P r o fil e.

Guideline Srudy Type MRID No. (year)/ Results No. C lassi Ii cation / Doses 870.4200 Carcinogenicity 44305304 (1992) NOAEL 

### = 3.4/4.4 m g/kg/day (M / F). ( rat ) Accep t able/ guideline LOAEL 

### = 27.7 / 39.4 (M/F), based upon M:O, 10 , 80 ,640,o r 1280 histopathology of the bone (osseous ppm hypertrophy of the cranium/parietal bone) , pale F: 0, 10 , 80, 640 ppm and thickened incisors, an d decrea se d abso lute M: 0, 0.4, 3.4, 27.7 , or 59 and relative adrenal and pituitary weights in mg/kg/day males; decreased body \Veight (at tenninal F: 0 , 0.6, 4.4, or 39.4 sacrifice) in females. mg/kg/day Dosing was considered adequate. No treatment-re lated inc reases in tumor incidence were observed. 870.4300 Carcinogenicity 44305305 ( 1998) NOAEL 

## = 1 .4 / 1.6 ( M/F) mg/kg/day. (mouse) Accep t able/ guideline LOAEL 

## = 12/ 14.5 (M/ F), based upon increased 0, 10,90,800,or 1250 liver weights and hepatocellular vacuolization ppm M : 0 , 1 .4 , 12, 1 1 8 , or in both sex es and increased kidney weights in 217 mg/k g/day males. F: 0, 1 .6, 14.8 , 140, or Dosing was considered adequate ba se d on 224 mg/kg/day above finding s. Treatment-related increa se d incidence of comb ined benign and ma l ignant liver tumors in both sexes. 870.5265 Gene Mutation 44 3355 11 ( 1987 ) Cyto toxicity was evident for the majority of Acceptab le / guideline s trains at ?: 1000 μg/p late -S9 and at 2000 125-2000 μ g/ plate ± S9 μ g/plate + S9. There was no evidence of activation. induced mutant colon ies over background. 870.5300 Forward gene 44335508 ( 1988 ) Cytotoxicity was observed in all trials at ?: I 00 mutation as s ay in Acceptable/guideline μ g/mL +/ -S9. There was no indication that M mammalian ce ll s 5-125 μ g/ mL ± S9 14360 induced a mutagenic re sponse, either in activation

. the pre sence of absence of S9 activation. 870.5375 Cytogenet ics 44335507 ( 1989) Cytotoxicity was observed at ?: 31.3 μ g/mL -S9 Acceptable/ guide line (6-hr. treatment and 24- hr. cell harvest or 2 4 0 .5-250 μ g/mL ± S9 hours of continuous treatment before activation

. sampling); 2: 15**~1 g/** **mL-S9** (48 hrs of continuous treatment before sampling) and at 2: 15.6**~tg/mL** +S 9 (6-hr. treatment and a 24-hr. cell harv est). Not clastogenic with or without S9 activa t ion , at any dose tested. 870.5395 in vivo 44335507 ( 1989 ) Cytotoxicity was observed at 2: 31.J**~tg/mL** -S9 mammalian Acceptable/ guideline (6-hr. treatment and 24-hr. ce ll harvest or 24 cytogenetic assay 0.5-250 μ g/mL ± S9 hours of continuous treatment before activation. sa mplin g); 2: 15**~t g/** **mL** -S9 (48 hrs of continuous treatment before sa mpling) and at 2: 15.6 μ g/ mL + S9 (6-hr. treatment and a 24-hr

. cel l harvest). Not c lastogenic with or without S9 act i vation , at any dose tested. 870.5550 U D S sy nth esis in 44335510 ( 1989) Cytotoxicity was evident in all trials at 2: 64 mammalian cell Acceptable/ guideline**~t g/** **mL** +/ -S9

. The po s itive control s induced cultu re 0.25-512 μg/ mL ± S9 signi ficant and dose-related increa ses in UDS. activation No evidence of genotoxic effect under any test condition.

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Tab l e A.2.4. S u bchro n ic, C h roni c, a n d Ot h e r Toxicit y Profile.

Guideline Study Type MRJD No

. (year)/ R es ult s No. C las sification/Doses 870.6200a Acute 4804940 I (20 I 0) NOAEL = 50 mg/kg/day. neurotoxicity Acceptab le / guideline LOAEL = 200 mg/ kg/da y du e to decrea se d sc r ee nin g battery 0 , 50 , 200 , or800 motor ac ti v it y on day 0 in both sexes, and mg/kg/day clinical s ign s in female s including hunched po s ture , decr eased defecat ion , and / o r red o r yellow mate r ial on various bod y su rface s. 870.6200b Subchronic 48049402 (20 I 0) System ic NOAEL = 120 ppm (8.7 /9

.5 neurotoxicity Acceptab le / guidel in e mg/kg/day [M / F])

. scree nin g battery 0 , 40 , 120 and 640 ppm Systemic LOAEL = 640 ppm (45.9/50.7 (0, 2.89/ 3 .13' 

### 8.69 1 9 .46, mg/k g/day [M/ F]) based on absolute decreased or 45.92 / 50.67 mg/k g/da y body weights in female s. [M / F]) The neurotoxicity NOAEL is 640 ppm (45.9/ 50.7 mg/kg/day (M / F])

. The neurotoxicity LO AEL was n ot observed. 870.7485 Metabolism an d 44305307 ( 1993) Abou t 92.0-100. 7% of th e administered dose pharrnacokinetics Acceptable/ guideline was r ecovered in urine , feces. and tissues (rat) M & F :**~C** within 72 hours of dosin g . Absorption of pheny l]tetrac o na zo le o r [ 1 ' 1C]tetraconazole from the G. I. tract of rats [**•~c- tria** **zo le**  ]tetraconazol e wa s evident in both low- and high-dose animals were given sing le gavage based on th e hi gh leve l of urinary exc retion , do se of 5 or 60 mg/ kg. which ranged from 50.7-71.0 % by48 hours po st-do se . Onl y minor d ifferences were noted in the pattern of exc r etion between the sexes, lab e ls, and dose l eve ls . About 3-6 % of the do se was recovered in the carcass / ti ssues. Differences were noted maximum blood concentrations between the doses , sexes, and labe l. No di fferences were noted in the halflife

.

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T able A.2.4. S ub c hr o n ic, C hro nic, a n d Oth e r Toxicity Pro fi l e.

Guideline Study Type MR1D No. (year )/ Res u lt s No. Classification/Doses 870

. 7485 Metabolism and 45068403 ( 1992) Total recovery of radioactivity ranged from pharmacokinetics Acceptab le / gu ideline for 95% to I 02 % of th e administered dose. Most (rat) excretion , distribution and of the dose (75%) was recovered in the urine metabolic identification after 7 days. Feces accounted for 15 to 1 8% of portion of the study. the administered dose. Triazole was the major Single oral doses of**~C]** metabolite identified in the urine and feces. In triazole ring labe led M

- the urine M-14360 acid along with minor 14360 administered at metabolite of M-14360 alcohol and its do se level s of 5 or 60 glucuronide conjugate (M3) were isolated

. In mg/kg , urine and feces the feces, minor amounts of parent M-14360 , were collected from five the acid, and alcohol were isolated. Data rat s/sex/ do se for 168 suggest M- 1 4360 or it s metabo li tes do not hours at which time the se accumulate in the ti ss ues following single oral animals were killed and administration. 95-98% of the urinary and their tissues and organs fecal metabolites were identified. There is a were harve ste d. The qualitative and quantitativ e difference in the remaining five metabolite s in the ma les and females and the anima ls / sex/group were dose leve ls. Male rats produced more triazole killed at peak blood level s than females (65-67% of the administered dose of radioactivity occurring (AD) vs . 48% in females) in the urine, whi le at 8-28 hours of post urine of females had more of M-14360 acid. do sing and their tissues The sa me pattern was also see n in the multiple and organs were dosing studies, although the differences were harvested. Radioactivity not pronounced. I n the multiple dosing stud ies , was measured in urine, triazole (3.2-3.9% of the AD for males and feces , blood , tissu es, females at the low dose vs. 6.5

-6.8% for the organs , carcasses and cage high dose), M-14360 acid, M-14360 alcohol, washes from all animals. M-14360, M6 and others were reported while in the single dosing only triazole (5.6-10.4 % of the administered low and high do ses in both sexes) , M-14360 acid and M-14360 were reported. Ba se d on the re su lts , the s tudy authors po s tulated that cleavage of M-14360 to yield triazo le appears to be a major step through glutathione mediated path. A metabolic pathway was proposed where the initial step is the formation of an aldehyde intermediate of M-14360 following dea l kylation of the fluoro-alky l group of the molecule.

Page 23 of29Tetraconazole Scoping Document DP# 426702

T a b le A. 2.4 . S u bc h ro n ic, C h ro n ic, a n d Oth e r To x ic ity Pr o fil e.

Guideline Study Type MRID No. (year) / Results No. Classi ti cation / Doses 870.7485 Metabolism and 44268114 ( 1 990) Total recovered radioactivity ranged from 99% pharmacokinetics Acceptable / guide line for to I 14% for the phenyl label and 96% to I09 % (rat) sing le dose excretion and for the triazo le labe l of the AD. Most of the distribution. radioactivity was recovered in the urine , S in g le oral doses of 1 4C- par t icularly the triazole label. In the triazole Tetraconazole phenyl study , males excreted the radiolabel into the labe led or triazole ring urine more and faster than in the females. labeled were admin iste r ed Compared t o the pheny l labe l, more of the at dose levels of 5 or 60 triazole label was excreted at both doses in the mg/kg, urine, feces and ur ine. Radioac ti vi ty in the ti ssues was minimal expired air were collected and accounted for les s than I % in the phenyl for 168 hours and label. For the rriazole label 0.9% to 1.4% radioactivity in blood , radioactivity was recovered in tissues. I n the tissues, organs, carcass feces, more phenyl label (21-32 % ) than in the and cage washes were tr iazo le label ( 1 2- 1 6% of the AD) radioactiv ity detennined. was excreted. Male rats generally exc reted the rad io labe l into the feces faster than in the females for both labels. 870.7485 Metabo lism and 44268119 (1994) The test material was readily absorbed and pharmacokinetics Acceptable/guideline for distributed in the body within 8 hours after (ra t) excretion and distribution dosing and abou t 100.9 ± 4.0 % of the oftriazole labe led M- adm inis tered dose was recovered. Urine was 14360 following repeated the major route of excretion accounting for oral adm inistra ti on. nearly 87% of the AD after 7 days of exposure. Groups of rats received Most of the urinary radioactivity was excreted single oral dose of non- during the first 48 hours. Fecal elimination of radiolabe led M 14360 at 5 the r adioact iv ity was the next major route or 60 mg/kg for 14 days accounting for 12-16 % of the AD after 7 da ys followed by si ng le ora l of expos u re. Less th an I % of the AD was dose of[ 14C] triazole ring recovered in tissues. Sex has no effect on labe led M 41360; animals excre t ion and distribution. were placed metabolism cages where urine and feces were co ll ected and radioactivity in blood, tissues, organs, carcass and cage washes we re detennined upon sacrifice. 870.7800 lmmunotoxicity 48439401 (2011) Systemic NOAEL = 1 25 ppm (10 mg/kg/day). Acceptable/ guideline Systemic LOA E L = 1000 ppm (82 f / AFC 0, 20 , 1 25, I000 ppm groups and 77 f/NK groups) based upon (0 , 2 / 2, IO/ I0 , 82 17 7 decreased mean body we ight and food [AFC Group/ NK Group], consumpt ion. [F]) l mmunotoxicity NOAEL = 1000 ppm (82 f / AFC groups and 77 FINK g roups)

. l mmunotoxicity LOAEL was not es t ablished

.

Page 24 of29Tetraconazo le Scoping Docume nt DP # 426702

T a bl e A.2.4. S ub chro ni c, Ch r o ni c, a nd Other Toxicity Pro fil e.

Guid e lin e Stu dy T ype MRID No. (year) / R esu lt s No. C lass ifi ca tion / Do ses No n- Live r e nzy me 4475 1 310 ( 1998) Di etary ad mini st rati on oftetraconazole for 4 g uideline- induction Acccptable/ no nguideli ne weeks results in liver enzyme induction at dose rats In d ietatdosesofO, 10 , leve ls of 80 and 640 ppm. Indu ct ion at th e 80 , 640 ppm; th e positive 640-ppm dose level was s imil ar to that induced control was Ph e no barbit a l by phen o barbit a l at 75 mg/k g/day. (Na) salt , 75 m g/

kg/day for 4 week s . Non- Liv e r enzyme 447 5 1309 ( 1996 ) Tetrac onazol e ad mini s tration for 4 weeks g uideline

- induction Acceptable/ nonguideline results in liver enzyme induction. At d oses 2'. rats In di et at do ses ofO, 20 , 20 ppm in females an a ppare nt increases in 800 , 1250 ppm in the diet; microsomal protein , cytochrome P 450 , and th e positive control was eth y lm o rphin e N-d e methyla se were observed. Ph eno barbital (Na) salt , At all dose levels in males and females, 7- 75 mg/kg/day for 4 pentoxyresorufin 0-d e pe ntylase values were weeks. s tati s tic a ll y elevated. At 800 a nd 1 250 ppm, s tatistically significan t findings were typica ll y no ted

. How eve r, do se -respon se in creases were not apparent in th ese findings at the 1250 ppm level as compared to the low e r 800 ppm leve l. No n- In Vi vo 28-Day 48 93040 I (20 1 2) NOAEL 

### = 69 mg/k g/day. g uideline

- Mode of Ac ti on Accep tabl e / nonguidline LOAEL 

### = 132.6 m g/kg/da y based upon 111 ice Study (mouse) 0 , 90 , 400 , or 800 ppm (0, in creased ce ll pro lif e ration in th e li ver. 14.1-17.2 , 57.6-78.4, and I 1

4.2 -158. 9 m g/kg bw/ day [Ml)

Page 25 of29Terraconazole Scopin!!. Document DP /1 426702


### Attac hm ent 3: R eg iste red E nd -Use Prod ucts and Appli ca tion Scenarios/Rate s ( inform ation pr ov id e d b y 

### BEAD) Tabl e A .3 .I: S umm ary o f End-U se Pr o du c t s.

Produc t Type Trade Names (E PA Re g. No

. ) Tetraconazole Use Si t es Application Type: RE I Target Co ncentration Equipment Pest s EC Affianc e® (I 0 163-332) 0.667 lb s ai/iaal micro-emulsion Zolera with aBpro (66330-422) I

.75 lb s ai / eal field com. popcorn. com foliar s pray: 12 hours for all ac ti v itie s with the exception of20 days for EC Te t racona z ole 2 10 ME (80829-20) I.75 lb s ail ga l g rown for seed , soy be a n g round/ acrial/chcmigation detasscling corn gro wn for seed EC Do mark® 230M E (80289

-7) I.9 I bs ai/ga l E C Eminent® 125 S L (60063- 1 2) I lb ai /gal sugar beet. peanut. pecan fo liar spray 12 hours EC Eminent® ESP (80829- 18 ) I lb ai/izal g round/aerial/chcmigation fungu s EC Priaxo r® D (7969

- 361) 1 .9 lb s ai /g al soybea n foliar s pray: g round/aerial 1 2 hours EC Menl c® 125 ME (80289-8) I lb ai/gal subgroups I 3-07F and foliar spra y; 12 hours for all activitie s with the exception of7 days for 13-07G (except cranberry) 1?.round/aerial/chemigation table !!.rape activi ties of a irding. cane tying. and cane tuminl! nowable Minerva DuoTM (83070- 11 ) 0. 73 lb ai/g al pecan and s ugar beet foliar spray: gr ound/aerial 48 hours concentrate
Tabl e A.3.2: S umm ary o f A p pli c ation Scena rio

. Formulation App. Rate Ma x. Seasonal App. Type/Timing App. Rate ( lb Use Di r ections and Limitations (EPA R eg. No.) (lb ai/ ac re ) ai/acrc) soybean REI = 12 hours: RT1 2= not sp ecified (app. for control of soy bean ru st) to 7-2 1 days; Pl-ll1 = EC ( 1 0 163-332: 80829

- 20: 80289-7 ; 7969-361); foliar spray/up to R5 1 0.05-0

. 08 0

. 1 2-0. 15 not specified to 1 4 or 2 1 days; maximum of2-3 app li ca ti ons per seaso n: do not graze / feed micro -emul sion (6 6330-422) soybean foragen1ay 10 live s tock ; do not use on soybean varieties harvested for the immature pod field com. popcorn , com g rown for seed EC ( l 0 163

- 332: 80829

- 20: 80289- 7): RE I = 12 hours for all activities with the exception of20 days for detasse ling com grown for micro-emul s ion (66330 -4 22) foliar s pray /up to R3 0.05-0.09 0.09 seed; RTI = not s pecified to 7 day s; Pf-Il l = not specified to 7 days (2 1 day s for si la ge); maximum of 2 applications pe r seaso n sugar beet E

C (60063 -12 : 80829-18 ) foliar spray / not specified 0.06-0. 10 0. 10 REI = 12 hours: PHI = 14 days ; maximum of I application per season nowablc concentrate (83070-1 1) Pe anut EC (60063 -1 2: 80829-18 ) foliar spray/not s pecified 0.06-0. 10 0.4 1 4 RE I = 12 h ours: RTI = 14 days; PH I = 1 4 days (do not app ly within 14 days of diggin g); maximum o f 4 application per seaso n; do not feed peanut hay to li vestock Pecan EC (60063- 1 2 ; 80829- 18) fol i ar s pray/ variou s 0.05-0. 13 0.50 RE I = 12 hours; RTI = 1 4 days ; Pl-I I = 30 day s : maximum of 4 application per s eason now ab le concentrate ( 83070-11 ) 13-07F EC (80829

- 8) fo liar sp ray / var iou s 0.02-0.04 0

. 08 RE I = 12 hours for all activities with th e exception o f7 day s for table grape activitie s of

Pa g e 26 of29Tetraco n azo le**Sc opin** **~** D oc um e nt DP # 4 267 02

Tabl e A.3.2 : S umm a ry of Appli ca ti o n Sce n a ri o. Fon nulati o n /\pp

. Rate M a x . Seaso nal ( E

P

/\ R eg . No

. ) App

. Typ e ffimin g ( l b ai/ acre) Ap p . R at

e ( lb U s e Dir ec ti o ns a nd L imitati o ns ai/ac re) g ird lin g, ca ne t y in g a nd ca ne tumin g : R T I 

### = 1 0- 2 1 day s ; PH I = 14 days ; m ax imum o f 3 app lication s per season I 3

- 07G (e xce pt c r a nb e r r y) RE I = 12 h o urs for a ll ac ti v itie s with the excepti on o f 7 days fo r table g rap e act iviti es of EC ( 808 29-8) fo liar s pra y /va riou s 0. 02-0 .0 4 0

. 1 6 g irdlin g. ca n e t y in g an d can e turnin g ; RTI = 14-2 1 d ays: Pl II = 0 days: m ax imum of 4 appli ca tion s p er season 1 All l abe ls , ex c lu din g the Pri ax o r® D (7969

- 36 1 ) labe l , pro hibit ap p li ca ti o n aft e r th e R5 cr o p s tage; a r ev is ed Pri ax o r® D la b e l prohibitin g app l i cati on aft e r th e R5 crop stage i s reque st ed. On ly the P ri ax o r® D ( 7969

- 36 1 : 2 1 day s ) an d Affi anc e® { l 0 163

- 332: 14 days ) la be ls s pecif y a PHI. 2 B ase d on the a va i la

b le fi e ld trail d a ta, r ev i sed la be ls s peci fy in g a minimum retrea tm c nt inte rval o f I 0 days ar c r equ es ted ( 032 93 79

. T. Bl oe m , 2 3 -Jan- 2007 ; 4 6 82620 I

. d e r)

. 3 Onl y t h e Affian ce® ( 10 1 63-332 ) la be l s pec ific s a PHI : all labe ls proh ibi t appl i ca

ti on after the R3 cr op stage .**~** ll1 c Emin e nt® ES P (80 8 29- 18 ) label n eed s to be r ev i sed to s pec i f y a max imum sea s o nal a ppli ca ti o n rat e o f 0. 41 lb ai / ac r e rath e r th an 0. 81 2 lb ai / ac r c.

P ag e 2 7 of 2 9Tetracona z ole Scoping Document DP# 426702


### Attachment 4: IRL Sheet Summary of US and Internation al Tol erances and Maximum Re sidue Limits Residue Definition: 

# us Canada Mexic o' Co dex 40 CF R I 80.557(a): tctraconazolc ( l- [2-(2,4- l-[2-(2 , 4-dichlorophen y l)-3-( I , 1 , 2 ,2

- 

# -- None dichlorophenyl)-3-( 1 , 1 , 2 , 2- tctrafluoroethyoxy)propyl]-1 H-1,2 ,4 -tri azole tetrafluorocthox y) prop y l]-1 H-1 ,2,4 -tri azole) Tolerance (p om) / Maximum Res idu e limit (m1;lk?.) Commodity 

# us Canada Mexico ' Co dex Aspirated grai n fractions 1. 0 

# -- -- 

# -- Beet s u gar, dried pulp 0. 1 5


# -- -- -- Beet sugar, molasses 0. 15 0

. 15


# -- -- C3eet s ugar, root 0.05 0.05 

# -- -- Cattle. fat 0. 15 0

. 02 

# -- -- Cattl e, liver 1.5 0

. 05 

# -- -- Cattl e. meat 0.0 1 0.02 

# -- -- Cattl e. meat byproduct s (except liver) 0. 15 0.02; 0.02 kidney


### -- 

# -- Com. field. fo rage I.I 

# -- -- -- Co m. fi eld , grain 0 .0 1


# -- -- -- Com, field, s t ove r 1. 7


# -- -- -- Com. pop, gra in 0.0 1 

# -- 

# -- -- Co rn , pop, s tover 1.7 

# -- -- -- Eggs 0.02 

# -- -- 

# -- Goat, fat 0. 15 0.02


### -- 

# -- Goat. liver 1.5 0

. 05 

# -- -- Goat. meat 0.0 1 0.02 

# -- - - Goat, meat by produc t s (except li ve r ) 0. 15 0.02 ; 0

. 02 kidney


### -- -- Ilo g. fat 0.0 1 0.02 

# -- -- Hog, liver 0.05 0.05 

# -- -- Ho g, meat 0 .0 1 0.02


### -- -- H

og. meat byproduc t s (except liver) 0.0 1 0.02; 0.02 kidney


### -- -- Hor se, fat 0.15 0.02 

# - - -- H

orse. li ver 1. 5 0.05 

# -- - - Ilorse. m ea t 0.0 1 0

. 02


### -- 

# -- Ilorse. m ea t byproducts (excep t li ver) 0. 15 0.02; 0.02 kidne y 

# -- -- Low growing berry s ubgr oup I 3-07G, 0.25 b e arberries , bilberries , lowb u s h blueberries, except cr an

be rry 0.25 cloudberries, cranberries, lingonberries , 

# -- -- muntrics , partridgeberries , strawberries Milk 0.03 0.01


### -- -- Milk. fat 0.7 5


# -- -- -- Peanut 0.o3


### -- 

# -- -- Peanut. oi l 0. 1 0


# -- - - -- Pecan 0.04 

# -- -- -- P

oultry. fat 0.05


### -- 

# -- -- Poultry

. m eat 0.0 1


### -- 

# -- -- Poultry meat byproduct s 0.05


### -- -- -- Sheep , fat 0. 15 0.02


### -- -- Sheep. li ver 1.5 0.05


# -- -- Sheep, meat 0 .0 1 0.02 

# -- -- Sheep, m eat byproducts (except li ver) 0. 15 0.02; 0.02 kidne y 

# -- -- S m all fruit vine climbin g. except fu zzy 0. 2 0.2 amur river grapes, gooseberries , grapes, kiwifruit. subgroup I 3-07F hard y kiwifruit , ma ypop , sc hi sa ndra berries 

# -- - - Soybean, r e fined oil 0.80 

# -- -- -- Soybean, seed 0. 15 

# -- -- -- Pa ge 28 of29

### Tetraconazole Sco pin g Document DP# 426702

Summary of US and Internat iona l Tol erances and Maximum R es idu e Limits Residue Definition: 

# us I Canada 

## I Mexico• 

## I Codex Comple ted : M. Negussie; 06 / 11 / 15 1 

### Mexico adop ts US tolerances and/or Co dex MRL s for it s export purpo ses.

Page 29 of29