## Registration Decision for the New Active Ingredients, Nitrogen dioxide and Dinitrogen tetroxide

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### Regi s tration Decision for th e New Active In g redient s, Nitrogen dioxide and Dinitrogen tetroxide

S umma ry The U.S. Envi ronm e ntal Prot ect ion Agency (EPA) is regi ste ring a new end -u se product containing two new active in g redients , d initr ogen tetroxid e and nitrogen dioxide (N02), under the Federal Insecticide , Fungicide, and Rodenticide Act ( FJFR A), as amended. Nitrogen dioxide and dinitrogen tetroxide are formulated into an end

- use product , Noxil izer N02 Steri lant, for u se as a gaseo u s steril an t in industria l , com mercial, and in st itut iona l settin gs on laborat ory equipment , isol ators, medi cal devices , pharmaceuticals, and pharmaceutical equipment. oxil izer 0 2 S teril ant is not labeled for use in steri le reprocessing of reusable medical devices. Background On August 6, 20 14, EPA received an applicat ion from Noxi li ze r, Inc. t o register an e nd-use product (Noxilizer N02 Sterilant) containing th e new active ingredient s, dinitroge n tetroxide and nitrogen dioxide (CAS Numbers I 0544-72-6 & I 0 I 02

- 44-0) , for use as a sterilant. Noxilizer N 0 2 Sterilant may only be used with Noxilizer lic ense d N02 generators or Noxilizer branded Sterilizers. These two device s have a sta ndard ope r ati ng manual which ca ll s fo r a 90 minute exposure time. Once instruments have been exposed , then the chamber has to ae rate before the doors can be opened. The company submitted product chemistry, efficacy, toxico logy, human exposure, ecological effects, and environmental fate data in support of its application for registration of the one end

use product containing th e new active ingredient s. Publi c Co mm e nt s As r equired by Flf-RA, the Agency pub li s hed a notice of receipt of an ap plicati o n to regi ste r a pesticide product co ntainin g the new ac ti ve ingr ed ients , nitro ge n dioxide and d in itrogen tetroxide , in the Federal Register on December 04. 2013 (78 FR 25596 ), and a 30 day public comment period comme nc ed. One anonymous comment was recei ved in re sponse to the Federal Register not ice. Comment: The sole commenter stated oppos iti on to the registration ' · of these new active ingredi e nt s." The co mment e r state d that it was crucial to assess "a ll possible complications with agr iculture related chemica ls due to synergy betw ee n these new ingredi e nts and o ther chemicals present in both our terrestrial and aquatic world." EPA R espo nse: The propos ed use of nitrogen d iox ide is as an an timi c rob ia l pesticide fo r s terilant use in medical, pharmaceutical , and lab ora tory sett in gs. Env ironment a l expos ure is minim a l and is mitigated through the use of scrubbers that remove most of the nitrogen dioxide during the Page 2 of6discharge process. The amount discharged after passing tlu-ough the scrubbers is below the ambient levels of nitrogen dioxide naturally occuning in the environment. The agency i s not aware of any data re ga rding the sy n e rgy ofN02 with agricultural or other chemicals, but if such information becomes available , the agency would review and assess any impact of such data on terr es trial and aquatic organisms. The Agency so u g ht public comment under the public participation process, FIFRA section 3(c) 4, for the propo sa l to i ssue an unconditional r egistr a ti on fo r Noxilizer N02 Sterilant on March I 0, 2016, and a 30 day public comment period commenced. No comments were received
. Eva lu at ion In evaluat ing a pesticide registration appl icat ion, the EPA assesses a wide variety of ex po s ure information , (i.e
. , where and how th e pesticide is used) , environmenta l fate ( i. e . , how the chemical will move in th e environment), and toxicity s tudi es and waiver rationales (i.e
. , effects on humans and other non-target organisms) to determine the likeliho od of adverse effects (i.e
. , ri sk) from exposures associated with the proposed use of the product. Ri s k assessments are d eve loped to evaluate the environmental fate of the compound as well as how it might affect a wide range of non-target o rgan i sms including hum ans, terrestrial and aquatic wi ldli fe (p l ants and a nimal s)
. On the basis of these assessments, EPA eva lu ates and approv es langua ge for each pe st icide label to ensure the directions for use and safety measures are appropriate to mitigate any potential ri s k
. The pe s ticid e's label communicates directions for us e that are neces sa ry to prevent unrea so nable adverse effects
. It is a F IFRA v io l at ion to use a re g istered pesticide in a m ann e r incon s istent w ith it s l abe lin g. 1. Assessment of Risks to Human Hea lth EPA require s a wide range of in formation in order to assess human health ri s k from exposure to a pesticide. The human h ea lth effects and risks of N02 from its u se as a s terilant are assessed in the February 1 I , 2016 document entitled, " Revised Risk Assess m en t for the New Active Ing redien t N itrog en Dioxidefor use as a Steri/ant" (see Docket 10: EPA-HQ-OPP-20 13-0792). The toxicity database to assess risk from exposure to nitrogen dioxide i s adequate to support the u se of nitrogen dioxide as a gaseous s terilant. For the use ofN0 2 as a gaseous ster il ant, exposure is expected to occur only for workers handling the product in an occupational sett in g. Residential u se i s not allowed and there i s no potential for food or drinking water exposure from the sterilant u se . Inhalation occupational risk was assessed for two exposure scenarios assoc i ated with its use as a s t

e ril a nt: I ) peak (o n e hour) exposu r es to N02 during opening of s teriliz a tion chamber doors or i so l a tion units after treatment; and 2) average dail y (8 hour time we ighted average) exposure t o N0 2 potentially rele ased into the room a ir r es ultin g from multiple cycles of tr ea tment s and opening of s t e rili zation chambe r door (s) and isol a tion unit s during a s in g le d ay . Toxicity endpo int s were se lec ted for N02 to perform exposure and risk assess m e nt s for inhalation occupational exposure (see Table 2)
. Fo r the human health assessment, human e pidemiology studies that were most relevant to th e ex posure scenarios for th e use were selected, and provide th e basis for se lect ion of inhalation endpoints , with anima l s tudies providing support Page 3 of6in the weight of ev id ence. Epidem i o l ogy studies we re used as th e basis fo r endpoint selection because the data showed a strong association between exposure to N02 and respiratory effects , particularly the exacerbati on of asthma
. Epidemio logy s tudie s also provided information on responses in suscept ibl e subpopulations
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## - ummary o OX I CO og 1 ca • n 1pom s or 1 rogen IOXI e Exposure Do se u sed in U ncertainty Study and Toxicological Effects Scena rio risk assessment Fae tor (s) 1 Acute (I hour) I 00 ppb I Ostro et al. (200 I) a nd Linnet al. (2000; TWA astluna -r e l ated effects) 8 hour TWA 34 ppb I Str ak et a l. (20 12); Delfino et al. (2002) (increase in resp iratory symp toms)

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n detennmmg uncertamty factors for nsk assessment, EPA cons r ders both the r eiatronsh1p of the response m experimenta l animals to the human response (i nt erspecies extrapolation) , and variab ili ty in response among the human population (int r aspecies variation). In the absence of information suggesting otherwise, a I0-fold uncertainty factor for interspecies extrapolation and a I0-fold uncertainty factor for inrraspecies variation is used by EPA , for a total uncertainty factor of I00, to accoun t for these uncertainties. In this risk assessment for N0 2 , the uncertainty factors were reduced based on the use of human epidemio l ogy data as the basis for the endpoints of concern. There was no need for an in te r spccies ext rapo lation uncertainty factor to extrapo l ate from animals to humans (the inters pecies extrapolation factor was reduced to I x) , and the intraspecies var i at ion factor (variabi li ty within the human population) was reduced to I x, as the endpoints of concern se lected for the acute a nd daily TWA inh a lation hazard were conservative, representing responses in the susceptible subpop ul atio ns of concern (asthmatics and ch il dren)
. The total un certainty facto r for this risk assessment was therefore I x. Human health risk conclusions from the use ofNox ili zer are summarized as follows: Peak Exposure
. Steri li za tion worker inhalation exposures to N0 2 from opening of the i solator or s teri li za ti on chambe r door(s) a r e not lik e ly to be of risk concern. The maximum measured concen tration dur ing the period of highest exposu re (i.e
. door open in g) was 177 ppb for the isolator and 1 58 ppb for th e ste rili zation chambe r. Although these values are above the acute endpoi nt value of 1 OOppb, they represent maximum exposures occuning over a span of on ly a few minutes from open in g of the isolator or ster ili zat i o n chamber doors. By compar i son, the endpoi nt va lu e of I OOppb represents a 1 hour TWA. In li ght of the fact that exposure from open in g of iso l ator or sterilizat i on chamber doors occurs for only a few minutes afte r eac h ster il ization cycle of 90 minutes, the average exposure over any one hour per i od would not likely exceed lOOppb. Average Daily Expos u re . Sterilizat ion worker 8 h our TW A exposures for th e iso l ator unit i s 35 ppb , w hi c h exceeded EPA's LOC of34 ppb
. Poten ti al expos ure can be reduced to 29 ppb (below E P A's LOC) ifthe room vent il at i on rate (ai r c h anges per hour [AC H ]) is in c r eased to 5 ACH o n the product labeling. Ster ili zation worker 8 hour t im e weig hted average (TWA) exposur es for the ster ili zation chambe r i s 23 ppb, whic h is less than the LOC of 34 ppb and i s not of concern.

2. A ssess ment of Eco lo gical Risk Page4of6Ba s ed o n th e u s e pattern o f No xilizer N0 2 S terilant , N0 2 will not re s ult in an y addition a l e x pos ure to th e e nviro nm e nt be c au se th e s teril ant w ill be c o nt a in e d in th e s t e rili za ti o n equ ip men t. In additi o n , a ir sc ru bbe r s ar e r eq uir e d to be u sed as a safe ty meas ure to re m ove N0 2 durin g th e di sc harge p rocess w hi c h w ill pr ecl ud e acc id e nt a l r e l

ease to th e e n v iro nm e nt a nd ex pos ure to no n-targe t o rga ni s ms . Th e amo unt di s char ge d afte r p ass in g thr o ug h th e s crubb e rs is be low ambi e nt level s ofN0 2 naturall y oc c urrin g in the e nvironm e nt. Ther e f o r

e, N 0 2 expo s ure fr o m th e u se o f this produ c t s ho uld n ot c au se any adver s e e ff ec t s to non - tar ge t o rg anism s . All aqu a tic , av ian , a nd terres tri a l pl a nt ec o log ica l ef f ec ts s tudi es have been wa i ve d
. 3. As sess m e nt of Efficacy EPA re quires e fficac y d ata to s upport antimi c ro bi a l pe s ti c id e product reg i s tr a ti o n s that mak e s pe cifi c public he alth c la im s aga in s t mi c roo rga ni s m s that a rc inf ec tiou s or p ath oge nic to man o n labe lin g s uc h as sa niti ze r , s t e ril ant , v iru c id e , o r di s in fec t a nt. Th e ef fi cacy of N itroge n Di ox ide is assessed i n the Ja nu a ry 23, 20 15 doc ume nt en titl ed , "Efficac y Re vi ew for N oxilize r N0 2 Sterilant, EPA File Symbol 8 926 5-R
.. (see Doc k et 10: E PA -H Q -OPP- 20 13

- 0792). The 1\0AC S poricidal T es t is r e quired f o r v a lidating s terili z in g c laim s . Any product makin g sp o ri c id a l o r s te rili z in g c l a im s must s ubmit da ta ag ain s t sp o res of both Bac illus s u b tilis (A T CC 1 9659) a nd Cl os trid i um spo roge n es (A T CC 35 84 ) o n 3 pro du ct sa mpl es re prese ntin g 3 di f f e re nt ba tc h es . o ne of w hi c h is a t leas t 60 days o ld (240 c arri ers pe r sa m p le; a to t a l o f 720 ca rri e rs)
. A ny s t eril iz in g agent ( liqui d , va po r, o r gas) th at is r e c o mm e n de d f o r u se in a s pe cifi c dev ice mu s t be t es t e d by th e A OAC S poricid a l T es t in th at s pe c ifi c dev ice in acco rd a nce with th e dir ec tion s f o r u s e . Sixty c a rri e rs, repre se ntin g e ach of 2 typ es of s urface s (p o rce la in peni cy lincl e rs a nd s ilk s utur e loo ps ), mu s t be tes te d. A pro du c t mu s t dem o n stra t e killin g o n a ll 720 carrie rs ; no fa ilur es a re pe 1mitte d. V a lid a ti o n da t a co nfim1in g th a t the prod uc t is ef fi cac io u s a s a s t e ril ant mu s t be co nduct e d u s in g a seco n d , ind e pe ndent la bo rato r y ( oth e r th an th e la bor ato ry th at de ve lop ed th e o ri g inal d ata)
. T he confirm a to ry d ata re quire s th e utilization o f o ne s amp le of th e product to b e t es t e d again s t b o th B ac illu s s u b tilis ( A T CC 19659) and C l os trid ium spo ro ge n es (A T C C 3 584 )
. Thirt y carri ers , re pr ese ntin g eac h of th e 2 types o f s urfac e s (s ilk s utur e loops a nd p orc e la in pe ni cy lind e rs) mu s t be tes t ed
. A prod u c t mu s t de mons tr at e killin g o n a ll 30 ca rri ers ; no f a ilu res are pe nnitt ed. Thi s s t e ril ant may o nl y be u se d with Nox ili ze r li ce ns e d N 0 2 ge n e ra tors o r Nox ili ze r brand e d Steriliz e rs . Th ese two de vi ces have a s tandard op e ratin g manu a l which c a ll s f o r a 9 0 minut e ex p os ur e tim e. Onc e in s trum e nt s hav e bee n ex pose d , then th e c hamber h as t o ae rate be f or e th e d oo rs ca n be o pe ne d
. Th e s u bm itt ed A O AC S p o ri c id a l A cti v it y T es t d ata a nd th e S po ri c idal Ac ti v it y Co nfirm ato ry T es t da t a de mon s tra t e d th a t Nox iliz er N 0 2 S t e ril a nt is an effec ti ve steril a nt by s ho wing 100 % kill or no grov v

th of B. s ubtili s and C. s poro ge n es in 750 carri e r s (720 carrier s s tandard s po ri c id a l t es t d ata and 30 carri e rs from th e co nfirmato ry tes t d ata) w hen u se d o nl y w ith Nox ili ze r prod uce d o r li ce n sed e quipm e nt at 20 mg/L in N0 2, in a 75 % pre -humidified c losed sys t e m , follow in g 90 minut es ex pos ure time o r g rea ter , at roo m t e mpe ratu re , f o ll owed by a n ae r at i o n tim e.
Page 5 of6R eg ulat ory Deci s ion U nd e r Sect io n 3(c)(5) of the Federa l In secticide , fun g icide and R ode nti c ide Ac t (F I FRA), th e Agency is un co nditi ona ll y re g i s t e rin g a new end-use product , Nox ilizer N02 Ster il an t , comprised of new active ingredients , nitrogen dioxide and dinitrogen tetroxide. The product label ha s been r ev i sed to increase the room venti lati on r ate to 5 ACH to miti ga t e the ri sk to hum a n s from inh a l atio n expos ur e to N02. The re gistr at io n is summari zed below: 89265-1 (Nox li zer N02 Steri la n t) • 99.5% Ni trogen dioxidc / dinitrogen t e tr ox id e • End-use Product , use as a gaseous sterilant in industrial , commerc i a l , and institutional se ttin gs o n , labo r ato ry eq uipm e nt , i so lat o r s, m ed ica l d evices, pharmaceut ica l s, a n d pharmace uti cal equipmen t The risk assess me nt s u pporting thi s de c i s io n can be found in th e r eg ulat ory docke t (Doc k et ID: EPA-HQ

- OPP-20 1 3-0792).

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