Z/V/on TM P - Volum e 5 - Decembe r201 3 Pag e 3 1 o f 3 9

EP A BIOPESTICIDE S AN D POLLUTIO N PREVENTIO N DIVISIO N COMPAN Y NOTIC EO FFILIN GFO RPESTICID E PETITION S PUBLISHE D I N TH E FEDERA L REGISTE R EP A Biopesticide s an dPollutio n Preventio n Divisio n contact : Dris s Benmhend , 703-308

- 9525 , benmhend.driss@epa.gov . INSTRUCTIONS : Pleas e utiliz e thi s outlin e i n preparin g th e pesticid e petition . I n case s wher e th e outlin e elemen t doe s no t apply , pleas e inser t

"NA-Remove " an dmaintai n th e outline . Pleas e d o no t

chang e th e margins , font , o r forma t i n you r pesticid e petition . Simpl y replac e th e instruction s tha t appea r i n green , i.e. , "[inser t

compan y name], " wit hth e informatio n specifi c t o you r action . SUBMISSION : E-mai l th e complete dtemplat e to : hollis.linda@epa.gov . TEMPLATE : DS M Foo dSpecialtie s B.V . Petitio n numbe r

t o b e assigned . EP A ha s receive dapesticid e petitio n(T o b e assigned ) fro mDS M Foo dSpecialtie s B.V. , Alexande r

Fleminglaa n 1 , 261 3 A X Delft , Th e Netherlands , proposing , pursuan t

t o sectio n 408(d ) o f

th e Federa l Food , Drug , an dCosmeti c Ac t (FFDCA) , 2 1 U.S.C . 346a(d) , t o amen d4 0 CF Rpar t 180 . (Option s (pic k

one ) NA-Remove : 1 . b y establishin g atoleranc e fo r residue s o f NA-Remove : 2 . t o establis ha nexemptio nfro mth e requiremen t o f atoleranc e fo r 3 . t o establis ha namendment/expansio no f a nexistin g toleranc e exemptio nfo r th e (Option s (pic k

one ) NA-Remove : 1 . microbia l pesticid e [inser t nam e o f activ e ingredient ] 2 . biochemica l pesticid e (6,ll,28-Trioxatricyclo[22.3.1.05,7]octacosa-8,14,16,18,20

- pentaene-25-carboxyli c acid , 22-[(3-amino-3,6-dideoxy-p~D-mannopyranosyl)oxy]-l,3,26

- trihydroxy-12-methyl-10-oxo- , (1R,3S,5R,7R,8E,I2R,14E,16E,18E,20E,22R,24S,25R,26S)- , CA S Registr y No . 7681-93-8 .Zivion TM P - Volum e 5 - Decembe r201 3 Pag e 3 2 o f 3 9

NA-Remove : 3 . plant-pesticid e [inser t nam e o f activ e ingredient ] i n o r o n [inser t commodity] , Pursuan t t o sectio n 408(d)(2)(A)(i ) o f FFDCA , a s amended , DS M Foo dSpecialtie s B. V ha s submitte dth e followin g summar y o f information , data , an dargument s i n suppor t o f thei r pesticid e petition . Thi s summar y wa s prepare db y DS M Foo dSpecialtie s B . V . an dEP A ha s no t full y evaluate dth e merit s o f th e pesticid e petition . Th e summar y ma y hav e bee n edite db y EP A i f th e terminolog y use dwa s unclear , th e summar y containe dextraneou s material , o r th e summar y unintentionall y mad e th e reade r conclud e tha t

th e finding s reflecte dEPA' s positio n an dno t th e positio no f

th e petitioner . I . DS M Foo dSpecialtie s B.V . Petitio n Summar y Petitio n numbe r

t o b e assigned . A . Produc t

Nam e an dPropose dUs e Practice s Th e Natamyci n activ e ingredien t (AI) , apolyen e macrolid e antimycoti c biochemica l substance , wa s discovere di n asoi l sampl e obtaine dnea r Pietermaritzbur g i n th e stat e o f Nata l i n Sout hAfrica . Thi s biochemica l substanc e wa s foun dt o hav e broad , poten t antifunga l properties , bu t n o antibacteria l activity . Th e lac k o f antibacteria l propertie s i s a distinctiv e advantag e fo r afungicida l pesticid e becaus e the n ther e i s n o basi s fo r concer n ove r developmen t

o f resistanc e b y huma n pathogeni c bacteria . Durin g post-harves t

pineappl e packing , Natamyci n wil l b e use di n abroa dspectru m liqui dfungicida l formulatio n containin g approximatel y 4 % b y weigh t o f th e technica l grad e activ e ingredien t (TGAI ) a s astabl e aqueou s suspensio n o f crystals . Thi s product , Zivion TM P , i s designe dfo r th e contro l o f

mol dgrowt ho n pineapple s durin g shipmen t an d storage . Zivion TM P ca n b e applie da s adi p o r spra y (pourin g o r

cascade ) wit hwa x a s a post-harves t

treatment . B . Produc t

Identity/Chemistry \ . Identity o f

th e pesticide an dcorrespondin g residues . Natamycin . N o residue s othe r tha n Natamyci n wer e found . 2 . Magnitud e o f

residue s at

th e tim e o f

harves t an dmetho duse dt o determin e th e residue . Th e propose dus e i n th e presen t applicatio n i s fo r

th e contro l Fusariu moxysporum , PeniciUiumfuniculosum , Rhizophu s stolonifer , Aspergillu s niger an dThielaviopsi s paradox a o n pineappl e durin g shipmen t an dstorage . Zivio n Pan da n alternativ e formulatio n o f Zivion TM P designate da s Zivion TM A wer e applie dpost-harves t a t anomina l concentratio n o f 40 0 pp mi n th e treatmen t solutio n wit h0.2 5 Lo f Sta-Fres h298 1 foo dwax . T o obtai n replicate ddata , trial s wer e conducte dwit hvarietie s MD- 2 an dMontelirio . Zivion TM P maximu mresidue s wer e 0.935 2 mg/k g i n whol e pineapple , 0.069 2 mg/k g i n juice , 0.013 0Z/V/on TM P

- Volum e 5 - Decembe r 201 3 Pag e 3 3 o f 3 9 mg/k g i n meat , 1.164 4 mg/k g i n rin dan d0.179 6 mg/k g i n we t bran . N o residue s o f Natamyci nwer e foun di n contro l pineapples . N o metabolite s no r degradatio n product s o f Natamyci nwer e found . LC-MS/M S method s wer e use dfo r th e analyses . Quantificatio n o f Natamyci nresidue s wa s accomplishe drelativ e t o a n externa l calibratio n curve . Th e limi t o f Quantitatio n (LOQ ) fo r

th e Natamyci n residu e metho dwa s 0.0 1 pp mi n al l pineappl e fractions . Th e limi t

o f detectio n wa s assigne da s th e lowes t concentratio n withi nth e calibratio n curv e o r

0.25ng/ml . Th e analytica l metho dt o detec t an dmeasur e natamyci n residue s an dresidue s o f

metabolites , i f

the y wer e present , wa s full y validated . 3 . Astatemen t

o f wh y ananalytical metho do f detectin g an dmeasurin g th e level s o f th e pesticide residu e ar e no t

needed . A worst-cas e estimat e o f th e Natamyci n exposur e i n th e die t wer e calculate dusin g th e following : 1 ) Maximu mpineappl e consumption ; 2 ) Us e o f th e consumptio ndat ao f

th e mos t highl y expose dpopulatio n group ; an d3 ) Us e o f th e maximu mresidu e foun di n th e trial s i n an y treate djuic e o r mea t sample , rathe r

tha n th e mos t probabl e residue . O n thi s basis , calculation s fo r exposur e t o Natamyci n throug h consumptio no f

treate dpineappl e yielde daMargi n o f Exposur e (MOE ) o f

approximatel y on e million . Thi s ver y larg e worst-cas e MO Eclearl y establishe s th e safet y o f Natamyci n fo r

th e propose dus e o n pineapple . Becaus e th e MO Ei s s o larg e eve n whe n worst-cas e assumption s o f exposur e ar e made , a n exemptio n fro mtoleranc e rathe r tha n anumeri c toleranc e i s appropriate , an da n analytica l metho dfo r

detectin g an dmeasurin g pesticid e residue s i n pineappl e i s no t needed . C . Mammalia n Toxicologica l Profil e Acut e Toxicit y Profil e ACUT EORA LTOXICIT Y - Ra t Toxicit y Categor y II I Th e tes t substance , Natamycin , wa s evaluate dfo r it s acut e ora l toxicit y potentia l i n femal e albin o rat s whe n administere da s agavag e dos e a t aleve l o f

200 0 mg/kg . Th e stud y wa s terminate dfollowin g th e stoppin g rule s o f thi s procedure . On e o f

fiv e animal s die ddurin g th e study . Ther e wer e n o clinica l sign s o f toxicit y i n survivor s durin g th e study ; polyuri a wa s observe di nth e anima l tha t die do ntest . Ther e wa s n o effec t o nbod y weigh t

gai n i n animal s survivin g t o termination . Abnorma l necrops y finding s occurre donl y i nth e anima l tha t die do n test , an dpertaine dt o anogenita l area , lung s an dcontent s o f th e intestines . Th e acut e ora l LD S O wa s estimate dt o b e greate r tha n 200 0 mg/kg . ACUT EDERMA LTOXICIT Y -Ra t Toxicit y Categor y I V Th e tes t substance , Natamycin , wa s evaluate dfo r it s derma l toxicit y potentia l an drelativ e ski nirritanc y whe n asingl e dos e moistene dwit h1. 0 m Lo f deionize dwater/ g tes t substance , a t

aleve l o f

505 0 mg/kg , wa s applie dt o th e intac t ski n o f albin o rats . N o mortalit y occurre ddurin g th e study . Ther e wer e n o clinica l sign s o f toxicit y o r

sign s o fZivion TM P - Volum e 5 - Decembe r201 3 Pag e 3 4 o f3 9 

### derma l irritatio n a t

an y tim e throughou t

th e study . Ther e wa s n o effec t o n bod y weigh t gain , wit hth e exceptio n o f on e anima l tha t

faile dt o gai n weigh t

durin g th e firs t

week . Th e gros s necrops y conducte da t terminatio n o f

th e stud y reveale dn o observabl e abnormalities . Th e estimate dLD50 , a s indicate db y th e data , wa s determine dt o b e greate r tha n 505 0 mg/kg . ACUT EINHALATIO N TOXICIT Y - Ra t Toxicit y Categor y I V Th e tes t substance , Natamycin , wa s evaluate dfo r it s acut e inhalatio n toxicit y potentia l i n albin o rats . Fiv e male s an dfiv e female s wer e expose dfo r fou r hour s t o a n aeroso l generate dfro mth e undilute dtes t substanc e (fin e powder ) a t aleve l o f 2.3 9 mg/L . Ther e wa s n o mortalit y durin g th e study . Clinica l sign s include dactivit y decreas e an d piloerection , whic hwer e n o longe r eviden t b y Da y 3 . Bod y weight s wer e unaffecte db y exposure . Th e gros s necrops y reveale dn o observabl e abnormalities . A s indicate db y th e data , th e acut e inhalatio n LC5 0 i s greate r tha n 2.3 9 mg/L . EY EIRRITATIO N - Rabbi t Toxicit y Categor y I V A nacut e ey e irritatio n stud y wa s conducte do n thre e albin o rabbit s usin g tes t substanc e Natamycin . Th e tes t

substance , 0. 1 m Lb y volum e (43. 7 mg) , wa s place dint o th e conjunctiva ] sa c o f

th e righ t ey e o f eac hanima l selecte dfo r

testing . Al l treate deye s wer e washe dwit hroo mtemperatur e deionize dwate r fo r on e minut e immediatel y afte r recordin g th e 24-hou r

observation . A maximu maverag e irritatio n scor e o f 62.0 , severel y irritating , wa s obtaine d1 hou r afte r treatment , bu t

ther e wer e n o positiv e effect s exhibite di n an y eye s a t 2 4 hour s afte r treatment . Hence , th e initia l irritatio n scor e coul dno t b e maintaine dan dNatamyci n TGA I wa s assigne dt o Toxicit y Categor y IV . SKI N IRRTIATIO N - Rabbi t Toxicit y Categor y I V A primar y derma l irritatio n stud y wa s conducte do nthre e albin o rabbit s usin g tes t substanc e Natamycin . Ther e wa s on e intac t tes t sit e pe r animal . Eac htes t

sit e wa s treate d wit h50 0 m g o f

tes t substanc e moistene dwit h0. 5 m Lo f deionize dwate r

an dcovere dwit ha semi-permeabl e dressing . Th e tes t substanc e wa s maintaine di n contac t wit hth e ski n fo r

4 hours . Observation s fo r

derma l irritatio n an ddefect s wer e mad e a t 1 , 24 , 4 8 an d7 2 hour s afte r remova l o f

th e dressings . Base do n th e PI I o f

O.I , th e tes t

substanc e i s rate dslightl y irritating . Base do n th e score s a t th e 72

- hou r

observatio n only , th e tes t substanc e i s assigne dt o Toxicit y Categor y IV . SKI N SENSITIZATIO N - Mic e No t aSensitize r A ski n sensitizatio n stud y wa s conducte do n 3 group s o f 5 femal e mic e t o determin e i f tes t substanc e Natamyci npossesse s asignifican t potentia l t o caus e ski n sensitization . Fiv e female s wer e assigne dt o eac ho f thre e groups , designate dGroup s I - III . Th e tes t group sZ/won TM P - Volum e 5 - Decembe r201 3 Pag e 3 5 of 3 9 

### wer e treate dwit ha n appropriat e dilutio n(25 % o r 50% ) i n propylen e glyco l vehicle , o r undilute dtes t

substance . Eac hanima l receive d2 5 u Lt o th e dorsu mo f eac hear . Th e animal s wer e treate donc e dail y fo r thre e days . Afte r

atwo-da y res t

period , al l animal s wer e injecte dwit htritiate dmethyl-thymidin e i nth e tai l vein . Fiv e hour s later , th e animal s wer e sacrificed , an dth e drainin g auricula r lymp hnode s remove dan dprepare dfo r cel l suspensio nan dscintillatio ncounting . A vehicl e contro l grou p o f fiv e female s wa s ru n concurrently , treate di nth e sam e manne r wit hvehicl e onl y instea do f tes t substanc e o r dilution . A positiv e contro l grou p o f fiv e female s wa s als o ru nconcurrently , treate dwit h 90 % alpha-hexylcinnamaldehyd e i nacetoneroliv e oil . Th e tes t substanc e produce dastimulatio ninde x o f < 3 i n al l group s o f

tes t animals , an di s no t therefor e considere dasensitize r (define da s producin g apositiv e response) . Genotoxicity . NATAMYCI Nwa s teste di nth e Salmonell atyphimuriu mrevers e mutatio nassay Avit hfou r histidine-requirin g strain s o f Salmonell atyphimuriu m(TA1535 , TA1537 , TA10 0 an dTA98 ) an di nth e Escherichi acol i revers e mutatio nassa y wit hatryptophan-requirin g strai n o f Escherichi acol i WP2uvr A . Th e tes t wa s performe di n tw o independen t experiment s i n th e presenc e an dabsenc e o f

S9-mi x (Aroclor-125 4 induce dra t live r S9-mix) . Base do n th e result s o f thi s stud y i t

i s conclude dtha t

NATAMYCI Ni s no t

mutageni c i nth e Salmonell a typhimuriu mrevers e mutatio nassa y an di nth e Escherichi acoi l revers e mutatio nassay . NATAMYCI N(88.9 % purity ) wa s teste dt o determin e th e numbe r o f chromosom e aberration s i nculture dperiphera l huma nlymphocyte s i nth e presenc e an dabsenc e o f a metaboli c activatio nsyste m(Aroclor-125 4 induce dra t live r S9-mix ) . NATAMYCI Ndi d no t induc e astatisticall y significan t o r biologicall y relevan t

increas e i nth e numbe r

o f cell s wit hchromosom e aberration s i nth e absenc e an di nth e presenc e o f S9-mix , i ntw o independentl y repeate dexperiments . NATAMYCI Ni s no t clastogeni c i nhuma n lymphocyte s unde r

th e experimenta l condition s describe di nthi s report . Reproductiv e an dDevelopmenta l Toxicit y Natamyci n(a s Delvoci d5% ) wa s administere ddail y durin g day s 6-1 8 o f gestatio nb y ora l intubatio n to group s o f

1 5 to 1 9 femal e Dutc hBelte drabbit s a t concentration s o f

0 , 5,15 , o r 5 0 mg/kg-da y . Th e administratio no f u p t o 5 0 mg/k g (bod y weight)-da y o f tes t materia l fo r 1 3 consecutiv e day s ha dn o clearl y discernibl e effec t o nnidatio no r

o nmaterna l o r

feta l survival . Th e numbe r

o f abnormalitie s see ni neithe r sof t o r skeleta l tissue s o f

th e tes t group s di dno t

diffe r fro mth e numbe r

occurrin g spontaneousl y i nth e sham-treate d controls . Fro mth e result s presente di nthi s repor t th e N o Observe dAdvers e Effec t Leve l (NOAEL ) fo r

th e teratolog y par t

o f th e stud y wa s establishe dt o b e 5 0 mg/kg/day . Subchroni c Toxicit y I na9 0 da y study , Natamyci nwa s administere ddail y vi ath e die t t o group s o f

2 0 Wista r rat s (1 0 male s an d1 0 females ) a t concentration s o f

0 , 125 , 50 0 an d200 0 ppm . Dietar yZivion TM P - Volum e 5 - Decembe r201 3 Pag e 3 6 o f 3 9 exposur e t o Natamyci nresulte di n n o treatmen t relate dfinding s i n th e 12 5 mg/kg/da y an d 50 0 mg/kg/da y dos e groups . Th e 200 0 mg/kg/da y dos e grou p ha dreduce dbod y weight s (male s an dfemales) , increase dalanin e aminotransferas e activit y i n individua l males , increase dure aan dinorgani c phosphat e value s (male s an dfemales ) an dpotassiu mvalue s (males) , an dreduce dcholestero l an dtota l protei n value s (females) . Fro mth e result s presente di n thi s repor t

th e N o Observe dAdvers e Effec t Leve l (NOAEL ) wa s establishe dt o b e 50 0 pp mNatamycin , equivalen t t o approximatel y 3 8 an d4 3 mg/kg/da y (correcte dfo r foo dscatter ) fo r

male s an dfemale s respectively . Toxicolog y Profil e - - Existin g U.S . Governmen t finding s o f

safet y Natamyci n(pimaricin ) ha s bee napprove db y FD A i n 2 1 CF RPar t 172 , Sec . 172.15 5 fo r us e a s adirec t

foo dadditiv e fo r

us e o n cheese . "Th e additiv e ma y b e applie do n cheese , a s a n antimycotic , i n amount s no t t o excee d2 0 milligram s pe r kilogra m(2 0 part s pe r

million ) i nth e finishe dproduct..." . Natamyci na s a5 % ophthalmi c suspensio n i s approve da s a n antifunga l dru g fo r

topica l ophthalmi c administratio n. I n 2 1 CF RPar t 573 , Sec . 573.68 5 FD A ha s approve dNatamyci nfo r us e i n broile r

chicke nfeed s a t

u p t o 1 0 gram s pe r

poun d o f foo d. Toxicolog y Profil e —Internationa l Finding s o f Safet y Th e Foo dan dAgricultura l Organizatio n o f th e Unite dNation s (FAO ) an dth e Worl d Healt hOrganizatio n(WHO ) throug hth e Join t FAO/WH O Exper t

Committe e o n Foo d Additive s (JECFA) , evaluate dNatamycin , mos t recentl y i n 2002 , fo r

safet y a s adirec t

foo d additiv e . Th e Committe e conclude dtha t "Althoug hus e o f

Natamyci na s a n antifunga l agen t i n foo dma y resul t

i n exposur e o f

th e endogenou s flor at o trac e quantitie s o f antimicrobia l residues , bacteri ai n th e huma n gastrointestina l trac t ar e no t affecte db y polyenes , an dth e Committe e conclude dtha t disruptio no f

th e colonizatio n barrie r i s no t a concern . Fung i ar e foun di nmuc hsmalle r amount s tha n bacteri ai nth e huma n < gastrointestina l tract , an dth e negativ e result s i n studie s o f acquire dresistanc e indicat e tha t selectio n o f

Natamycin-resistan t

fung i i s no t

a n issue . Th e Committe e confirme dth e previousl y establishe dAD I o f 0-0. 3 mg/k g b w fo r

Natamycin , whic hwa s base do n observation s o f

gastrointestina l effect s i nhumans. " Th e Anima l Metabolis mo f Natamyci n A s describe di n th e WH O evaluatio n , studie s hav e bee n don e t o determin e th e fat e o f Natamyci ni n rat s an ddogs . I n rats , aserie s o f studie s showe dtha t

th e materia l wa s no t absorbe dan dwa s eliminate di n th e fece s an durine . Th e result s o f th e autoradiographi c stud y indicat e tha t

Natamyci ni s minimall y absorbe dint o th e bloodstrea man dexcrete d almos t entirel y i n th e feces . Othe r experiment s gav e simila r results . I n th e stomac han d smal l intestine , Natamyci nwa s mostl y untransformed , a s indicate db y thin-laye r chromatography . Mos t

degradatio ntoo k

plac e i n th e larg e intestine . Th e degradatio n product s wer e mor e hydrophobi c tha nNatamyci nan dwer e foun dfro mabou t 4 hafte r treatment . Mos t

o f th e dos e o f

1 0 mg/k g wa s degrade dabou t 8 hafte r treatment , suggestin g tha t

eliminatio ni s relativel y rapid . Biotransformatio n wa s attribute dt o th eZ/w'on TM P - Volum e 5 - Decembe r201 3 Pag e 3 7 o f 3 9 bacteria l flor ai n th e caecu man dsmal l intestine . Overall , n o mor e tha n 5-7 % o f th e tota l radioactiv e dos e wa s absorbe dafte r ora l administratio n o f

[14C]Natamycin , an d approximatel y 90 % o f

th e administere dcompoun dpasse dthroug hth e gastrointestina l trac t withou t resorptio n an dwa s eliminate di n th e faece s . I n dogs , afte r ora l administration , mos t

o f th e radiolabe l wa s eliminate di n th e faece s withi n 2 4 h , wit hles s tha n 4 % o f

th e tota l dos e i n urine . Th e WH O assessmen t conclude dtha t

ther e wa s ver y littl e dat ao n humans , bu t on e stud y ha dshow n tha t "N o Natamyci n ( < 1 u,g/ml ) coul db e detecte di n th e bloo dafte r ingestio n o f

50 0 m g b y huma n subjects" , indicatin g tha t i t wa s unlikel y t o b e absorbe db y humans . D . Aggregate Exposure 1 . Dietary exposure . Natamyci n i s currentl y permitte da s a n FD A foo dadditive , an d i s approve da s a n antimycoti c fo r us e i n th e finishe dchees e a t aleve l o f

2 0 ppm . (Se e 2 1 CF R§ 172.155) . I t

i s als o allowe db y EP A fo r us e o n mushroom s withou t th e requiremen t fo r atolerance . Th e lowes t NOE Lfo r

Natamyci n i s 2 5 mg/k g bw/da y o r approximatel y 1.7 5 g/perso n pe r

day . Th e propose dus e i n th e presen t applicatio n i s fo r

th e contro l o f Fusariu moxysporum , PeniciUlu mfuniculosum , Rhizophu s stolonifer , Aspergillu s niger an d Thielaviopsi s paradoxa . o n pineappl e durin g shipmen t an dstorage . Th e applicatio n produce s Natamyci n residu e level s i n th e edibl e portion s o f th e pineappl e o f

0.069 2 mg/k g i njuic e an d0.013 0 mg/k g i n meat . 1 . Food . Th e highes t

annua l pineappl e consumptio n i n th e las t decad e wa s 14.1 6 pound s pe r

person . Th e highes t

foo dconsumptio n i s fo r th e 12-1 9 ag e group . Usin g th e highes t annua l pineappl e consumptio n an dth e media n weigh t i n fo r female s age d1 2 - 19 , th e averag e consumptio n woul db e 36 4 mg/kg.bw/day , resultin g i n aMargi n o f Exposur e o f approximatel y on e million . ii . Drinkin g water . Al l use s o f Zivion TM Pwil l b e post-harvest , an dnatamyci n ha s onl y ver y limite d(-30-4 0 pp ma t neutra l pH ) solubilit y i n water . Hence , exposur e throug h drinkin g wate r

i s no t expected . 2 . Non-dietary exposure . Th e onl y non-dietar y exposure s fro mpesticida l use s o f th e Natamyci n wil l b e occupational , i.e. , commercia l applicator/mixe r loade r exposures . Occupationa l exposure s ar e no t include dunde r

th e Federa l Food , Dru g an dCosmeti c Ac t (FFDCA ) i n th e assessmen t o f aggregat e exposure s fo r th e purpos e o f

establishin g tolerance s an dexemption s fro mtolerance . E . Cumulativ e Effects . I n assessin g th e cumulativ e effect s o f Natamyci n i t

shoul db e recognize dtha t

i t i s on e o f aclas s o f

polyen e antimycotic s naturall y presen t i n th e environment . Other s o f th e clas s ar e als o typicall y obtaine dfro msom e specie s o f Streptomyce s bacteria . Th e amoun t o f materia l likel y t o b e presen t a s residue s o f Natamyci n o n pineappl e result s i n s o smal l a n incrementa l exposur e a s t o b e negligible . F . Safely Determinatio nZ/w'on TM P - Volum e 5 - Decembe r201 3 Pag e 3 8 o f 3 9 1 . U.S . population . A s discusse dabove , whe n expresse di n pound s pe r day , pe r capit afoo dconsumptio n i s highes t amon g me n an dwome n age d12-19 . Whe n expresse do n akilogra mbod y weigh t basis , th e intake s fo r

al l individual s ar e al l withi nafacto r o f 2 , wit hth e 12-1 9 ag e grou p female s havin g th e lowe r bod y weight . 2 . Infant s an dchildren . O n auni t bodyweigh t

basis , ther e i s n o significan t differenc e i nchildren' s consumptio n fro mtha t o f th e averag e adult . G . Effect s o n th e Immun e an dEndocrin e System s Becaus e Natamyci n i s minimall y absorbe dint o th e bloodstrea man drapidl y excrete dalmos t

entirel y i n th e fece s wit hminima l degradation , effect s o n th e immun e an d endocrin e system s ar e no t expected . Th e limite dbiotransformatio n foun dwa s attribute d t o th e bacteria l flor ai n th e caecu man dsmal l intestine , an dth e degradatio n product s wer e mor e hydrophobi c tha n Natamycin . H . Existin g Tolerance s • Ther e ar e n o existin g U.S . tolerance s fo r Natamyci n a s apesticide . EP A ha s grante d a n Exemptio n fro mth e Requiremen t o f aToleranc e fo r

Natamyci n us e o n mushrooms . / . Internationa l Tolerance s N o internationa l tolerance s exis t fo r us e o f Natamyci n a s apesticide .