### UN I TE D STATES ENV IRO NMENT A L PR OTECTIO N AG E NCY WAS H ING T ON. D
. C
. 20460

MEMORANDUM DATE: December 2, 2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: N icarbazin
. Human Health Draft Risk Assessment for Re gistration Review
.

PC Codes: 085712 Decision No.: 505004 , 505007 Petition No.: N IA Ri s k Assess me nt Ty p e: Single Chem ica l Aggregate TXR No.: N / A MRID No.: NIA DP B a r code: 0427303 , 0427299 Registration No.: 80224-1 , 80224-2 Regulatory Action: Registration Review Case No.: 7628 CAS Nos. : 330-95-0 40 CFR: NA 

### FROM: Matthew Crowley , Biologist/Risk Assessor Risk Assessment Branch 

### J[ Health Effects Di v i sion (7509 P) Office of Pesticide Pro grams Christopher Sc hl osse r, T oxico log ist Risk Assessmen t Branch Vf Health Effects Division (7509P) Office of Pesticide Programs TH RO UGH: Chr i stina Swartz , Branch Chief Risk Assessment Branch 

### 1 1 Health Effects Division (7509P) Office of Pesticide Programs TO: Bonnie Adler , Chemical Review Manager Risk Management and Impl ementation Branch 5 Pesticide Re-evaluation Division Office of Pesticide Programs As part of R egistration Review , the Pesticide Re-evaluation Di v ision (PRD) of the Office of Pesticide Programs (OPP) has requested that th e Hea lth Effects Division (HED) determine the hazard and exposure data as well as the assessments needed to estimate human hea lth risk that will result from the current ly registered uses of pesticides. In the case of nicarbazin , a pigeon contraceptive , HED has determined that no additional data are needed , and therefore this memorandum serves as both HED ' s scoping document and draft risk assessment (DRA) for nicarbazin. The risk assessment was provided by Matthew Crow le y (RAB ii ) wi th hazard characterizati on by Chr istop her Schlosser (RAB V I ).N icarbazin D raft Risk Assessment DP No. D427303
Table of Conten t s 1.0 Executive Sununary
....................................................................................... . ... .. . .. .. .. . .. .. .. .... 3 2.0 11 ED Recommendations
.... . ....... . .. . ................................................................. . ...... .. .. . ............ 4 2.1 Data Deficiencies / Conditions of Registration
................................................................ 4 2.2 Tolerance Considerations
........................................................................... . ... . ............... 4 2.3 Label Recommendations
........................................................................ .. .. . .. .. . .. .. .. ........ 5 3.0 Introduction
................................................................................................. . .. .. .. . .. .. .. . .. .. ........ 5 3.1 Chemical Identity and Physical/Chem ical Characteristics
....... . ...... . .. .. .. . ....................... 5 3.2 Pesticide Use Pattern
........................................................................... . .. .. . .. .. .. . ... . .. ........ 6 3.3 Ant ic i pated Expos ure P athways
.. . ... . ... .. . ... . .......................... . ... . .. . ..................... . .. .. .. .. .. .. 6 3.4 Cons iderat ion of Environmenta l Just ice . . .. .. .. .. .. .. .. . ... . .. . ... .. .. .. . .. .. .. .. . .. .. .................... .. .. .. 6 4.0 l l aza rd C h a racterizati o n and D ose- R espo n se Assessment
............................ .. . .. .. .. . ... . .. . ... . .. . 7 5
. 0 E n doc ri n e D i s ru pto r Sc ree n i n g P rogram ................. .. .. .. .. .. ...... . ...... .. . ... . .. . .. .. .. .. ..... .. .. ............ 9 6.0 D ie ta ry Exposu re an d Risk Assess m e nt . ... . ... . ... . ... .. . .. ... . ... .. . .. .. .. .. . .. .. .. .. . ......... . ....... .. . .. . ... . .. I 0 7 .0 Res ident ia l (Non-Occupational) Exposu r e / Ri sk Characte rizat io n .............. .. .. .. .. .. . .. . ... . .. .. .. I 0 8
. 0 Non-Occupational Bystander P ost
- App l ication I nhalation Exposure and Risk Est i mates .. I 0 9.0 Non-Occupational Spray D rift Exposure and Risk Estimates
.......... . ... . .. . .. .. .. .. ................ .. . 1 1 I 0.0 Aggregate Exposure/ Risk Characterization ....................................... . ...... . .................. . .. . .. 1 1 11.0 Cumulative Exposure/ Risk Characterizat ion ...................................................... .. .. .. . .. .. . ... 11 12.0 Occupational Exposure/Risk Characterization
...................... . ................................ . .. . ... . ... 11 12.1 Occupational Handle r Exposure/ Risk Estimates
........................................... .. . .. .. .. . . .... 12 12.2 Occupational Post-application Exposure/Risk E stimates
.............................. .. ............. 15 13.0 Public Health and Pesticide Epidemiology Data
............................................................... 15 14.0 Refe rences ................ . .. .. .. .. . ... . ... . ... .. . ........................................... . ........................... . ... .. ..... 15 14.1 HED Memoranda
.. .. . ... .. .. .. . .. .. .. .. ........................................... . ....................... . .. .. ... . .. .. .. 15 14.2 Published Literature and Other Documents
.............................................. .. . .. .. .. .. .. ...... 16 Append ix A: Toxicity Profile and Executive Summaries ........................... . .. .. .. . .. .. .. .. .. . .. . ........... 17 A. I Toxico logy Data Req uire m e nt s . .. ... .. .. .. . ... . ... . ................................. .. . .. .. .. . .. .. .. .............. 17 A.2 " foxieity P rofiles
. .. .. . .. .. .. .. .. .. .. .. .. .. .. .. .. .. . ....................... . ...... .. .. .. .. . .. .. .. . ................. .. .. .. . .. 18

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### Nicarbazin Draft Risk Assessment DP No. 0427303 

### 1.0 Executive Summary 

### Use and Exposure Profile Nicarbazin is the active ingre di e nt in one registered end-use product , OvoControl P (EPA Reg. No
. 80224-1 ) , a 0.5% active in gredient granule/bait pigeon contraceptive packaged in a 30 lb bag. Use sites are limited to paved / concrete areas or rooftops of office parks , malls , hospital s, sc hools , bridges, airports, other commerc i al/industri al buildings/ structures. The l abe l spec ifies use in secured areas with li mited public access and for applicators to remove excess / un eaten bait o ne how- after app li cation
. Based on th i s use pattern, only dermal and inh a lation exposures are ant icipated for occupational handl ers (mixer/loaders and applicato r s); fo ll owi ng removal of excess/ uneaten bai t , occupational post-application exposures are not expected. Additionally, no dietary exposures via food and/or water nor any non-occupational/ residentia l exposures via app li cation, post-applicat ion, spray drift , or vo latilization are expected
. 

### Hazard/Toxicology Assessment Based on the available data submitted to the Agency and an available European Food Safety Authority (EFSA) report, the toxico logy database for nicarbazin is s ufficient for assess i ng risk. Nicarbaz in ha s low acute toxic ity, is a moderate eye irri tant, and is not a de rm al irri tant or sens itizer. Avail able studies did not indicate any concerns for neurotoxicity or immunotoxicity. No evidence of mutagenicity was observed. The lowest observed adverse effect level (LOAEL) of 1 8 1 mg/kg/day from the 90 -d ay rat oral toxicity study is considered appropriate for assessing ri sk for all exposure scenario s . A I 

### OX database unc ertainty factor was app li ed for a LOAEL to no observed adverse effect level (NOAEL) extrapolation , resulting in a 1000-fold 

### UF ( 1 

### OX for interspecies extrapolation , 

### IOX for intra spec ie s variation, and 1 

### OX Ufdb) for all exposure scenar ios. Nicarbaz in is a non - food u se chemical with no re s id enti a l u ses; exposure to ch ildr en i s not expected
. Therefore, add i ti onal safety factors according to the Food Quality Protection Act (FQPA) do not apply. 

### Aggregate Exposure and Risk In accordance with the FQPA, H E D must consider a ll routes of exposure , including from nonpesticidal sources, to estimate aggregate exposure (i
. e. , dietary (food and/ or drinking water) plus non-dietary / re s idential )
. Based on th e u se pattern for ni carbaz in , dietary and nondietary/ residenti al exposures from its pesticidal u se are not expected; thus an aggregate assessment is not appl i cable. 

### Occupational Exposure and Risk Th e quantitative exposure/ risk assessment developed for occupational handlers of nicarbazin is based on appl i cations of granules by hand or with hand-operated equipment such as a belly grinder or rotary spreader. There w ere no combined (de1mal + inh a lati on) risks of concern w ith
Pa ge 3of 1 9Nicarbazin Draft Risk Asse ss ment DP No. D 427303
labe l- spec ifi ed wo rk attire and p e rsonal protecti ve equipment ( PP E) (long s lee ve s hirt , pants , s h oes. socks, g loves)
. Environm e ntal .Justice Conside rati ons Po te nti al areas of e n viro nm e ntal justice concerns. to th e ex te n t possible, we re consider ed in thi s human he a lth ri s k assess ment , in accordanc e w ith U.S
. Exec uti ve Order 

### 12898 , ''Fe deral Actions to Address E n v ironm e ntal Ju s tice in Minority P opu lat ions a nd Low- Income Popu lati o n s." R ev iew**r~(** I!uman R esea rch This ri s k assess m e nt relie s in part on data from s tudi es in w hi c h adu lt human s ubject s were inte nti o n a ll y ex p osed to a pe st ic id e o r other chem ica l. T h ese d a t a , whic h include studies from the P est ic id e ll a ndl ers Expos ure Databas e V e r sio n 

### I. I ( PH E D 

### I.I ) a nd th e Outdoor Resid en tial Expos ure Task Fo rc e (ORETF) database ar e 

### (1) subjec t to e thi cs rev iew pur sua nt to 40 CFR 26, (2) h ave r ece iv e d that rev iew , and ( 3) are comp li ant wi th app li cabl e ethic s requireme nt s. For ce rtain s tudi es , th e e thic s r ev iew ma y h ave included rev i ew by th e Human Studies R ev iew Board. Descriptions of data so urces , as well as g uid a nc e o n th e ir u se , can be found at the Age n cy webs ites: http ://www2
. epa . gov/ pe s ticidc- s ci c ncc - and- asscss ing-pc s ticideri s k s /occupational-pe s ticide-handler

- exposure-data and hnp ://ww'.v 2
. e pa . go v/ pesticide

- sciencea nd

- a ss e ss i n g

- p cs t ic idc-ri s k s/ occupational

- pest icide-po s t-app I i c at ion-ex pos ure . 2.0 HED Recommendations H ED h as exa min ed a ll appl icab le database s for nicarba z in , a nd co n c lud es that there are no res idue c h e mi stry, occupationa l / residential , or toxico logy data d eficie ncie s that would preclude th e co ntinuation of it s registration. In te rm s of hum a n h ea lth ri sk concerns , only occupat ion a l h a ndl er exposu re s are expected a nd no risk s o f co n cern were id e ntified ass umin g lab e l-specified wo rk a ttire an d p e r s ona l protecti ve equip m e nt ( PP E) of long - s leev e shirt, long pant s, and g loves. Th e lack of any ri s k conce rn s in thi s assess m e nt wa s pa11ially due to th e assumption that th e labe l-requ ired gloves are chemicalr esis tant , d es pite th e lab e l o nl y spec if y in g ''g loves"
. T hu s, H E D recommends co nfirmin g and rev i s in g th e la b e l to s pecify u se of ' · chem ica l-res i s t ant g loves" during app li catio n and remova l of excess/ un ea te n bait , in addition to any other PPE r e quire m e nt s based on the e nd-u se product acute toxic ity profil e . 2.1 D ata Deficiencies/Co ndition s of Regi s tration There arc n o data deficiencies for nicarb az in. 2.2 Tolerance C on s id e ration s There a re n o p es ticid e tol e rances for nicarbaz in
.

P

age 4or 1 9

### Nicarbazi n Draft Risk Assessment DP No. 0427303 

### 2.3 La b el Reco m me nd ati on s The product label specifies wearing a long-sleeved shirt , long pants , shoes , socks , and gloves

- it does not specify whether the gloves should be chemical-resistant. This should be confirmed , both in terms of risk estimates described in this assessment assuming the exposure reduction provided by chemical-resistant gloves, as well as any other PPE requirements based on the enduse product acute toxicity profile
. 

### 3
. 0 In tro d uc tio n Nicarbazin was first registered as a pesticide by EPA in 2005 to reduce egg hatching in Resident Canada Geese. Nicarbazin interferes with the formation of the vitelline membrane , separating the egg yolk and egg white
. The exact mode of action is unknown , although it is thought nicarbazin interferes with cholesterol metabolism in the formation of the membrane. Eggs from treated birds are described as mottled in appearance , reflecting a porous vitelline membrane. The effect on hatchability is a function of time and dose and the effect is reversible. Nicarbaz in has been a Food and Drug Administration (FDA) approved veterinary drug for use as an anticoccidial agent in broiler chickens since 1955. FDA has established a tolerance of 4 parts per million for nicarbazin res i dues in uncooked chicken muscle , skin, liver , and kidney (21 Code of Federal Regulations 556.445). FDA has also established its use as a feed addit ive to prevent outbreaks of fecal and intestinal coccidiosis (21 Code of Federa l Regulations 558
. 366) (US EPA , 2005). Currently there is only one registered end-use product , OvoControl P (EPA Reg. No. 80224-1 , Innolytics, LLC) , a 0.5% active ingredient granule/ bait , used as a contraceptive for pigeons. U se sites are limited to paved/concrete areas or rooftops of office parks , malls, hospitals, schools , bridg e s, a irports , or other commercial/industrial bu i ldings/ structures. The label spec i fies use in s ecured areas with limited public access. 

### 3.1 C h em i ca l Ide nti ty a nd P h ys i ca l/Chem i ca l C h arac t eristics Nicarbaz in (Cl 9H l 8N606) is a complex of two compounds , 4 , 4'

- dinitrocarbanilide (DNC, 30 2 .25 molecular weight) and 4 , 6-dimethyl-2-pyrimidinol (HOP , 124.14 molecular weight)
. DNC is considered to be the active component , while HOP aids in absorption. Additional nomenclature and physical/chemical properties are provided below. Tab le 3 .1.1 C h e m ica l Nome n c l at u re a n d P h ys i ca l /C h e mi ca l P r operties of N i ca r baz in (US EPA, 2005) CAS # 330-95-0 Molecular wei g ht ( g/mole ) 426.38 Ph y sical state Yellow, fine powder M e lting point 265-275 ° C s lightly s oluble in dimethyl s ulphoxide (DMSO) and dimethylformamide (DMF) ; Aqueou s solubility insoluble in water and methanol , however it decomposes s lowly wh e n mi x ed with them pH 5

- 7 (I % su s pension in water) Den s ity ( g/mL) 0.5

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### Nicarbazin D raft R isk Assessment DP No. D427303 

### 3.2 P es ticid e Use Patte rn Table 3
. 3. 1 below outlines the use profile for O voCo ntrol P, th e o nl y e nd us e product registered co nt a inin g ni carba z in as the active ingredie n t. The m a nufa cturi n g/fo r mulating use product is EPA Re g. No . 8 0224

- 2
. T a bl e 3
. 3 .1 Nicarba z in Use Pro fil e (E PA Reg. N o . 802 24

- 1) Appli ca ti o n Wo r k Use Di r ecti o n s a nd Use S itcffa r ge t Fo rmul a tion Equipm e nt Atti re / Ra te PPE Limitation s Co mm erc ial a nd 0.5%ai
- Hand I ounce of Long 

## - Use only in secured indu s tri a l granul e /bait dispersal product p er 5 s leeve d areas wi t h limited buildings (e.g.,



### - Rotary pi geo ns s hirt. l ong public access. office pa rk s , spreader pant s,


### - Condition pigeon s over mall s, ho s pital s.



### - Be lly I o'Zi5 pi geo ns s hoe s, a period of 5 to 14 day s. sc ho o ls, brid ges, grin de r * 1 lb/ 16o z* soc k s , s tarting with small airports): 0 .5% = g loves . amounts of bait and rooftops o r 0.0000625 l b vis uall y observing paved / co nc r e t

e ai /pi geo n whether the pigeon s are ar

eas of limited feeding. public acce ss Product is a 30 Remove excess bait lb bag , enoug h 

### - to t rea t 2400 after each feeding. pigeons 

## - Di scont inu e use after 14 days if conditioning fails. 

### 3.3 Anti c ipated E xpo s ure Pathways B ased on th e u se pattern , dermal and inha lat ion exposures are a nticipated for occupational hand le r s only ( i.e., those who individua ls who load / apply th e product and remove excess/ uneaten ba it). Afte r app li cat ion and bait removal , no occupational po s t-app l ication expos ures are expected, n or a re a ny non-occ upat io n a l / res ide nt ial exposu r es e xp ec ted via appl icat ion, post
app l icat ion , s p ray d rift , o r vo lat ili zati on . Fo r occupational ha nd le r sce n a ri os , s hor t- and in t ermedia t e-term d u ra ti ons a r e expected; lo n g-term expos ure s a r e not ant icipate d
. 

### 3.4 Co n s ideration of Environm enta l .Ju s t ice Po te ntial a r eas of environmenta l justice concern s , to th e ex t e nt po ss ib l e, were considered in thi s hum a n hea lth ri sk assess ment. in accordance with U.S
. Executive Ord e r 12 898 , · ' Federal Actions to A ddress E nv ironme ntal Justic e in Minority Populati o n s a nd L ow- Inco me Populatio n s,' · ( http: //www . archi\'cs
. go\'/ federal

- reuis ter / exec u tive

- orders/ pdf / J2898.pd l). As a part of every pesticide ri sk assess ment , OPP considers a large vari e ty of co n s um e r s ub gro ups according to we ll- estab li s hed procedures. In line with OPP polic y, HED es tim ates risk s to popu l ation s ub grou p s from p es ticide exposures that are ba se d on p a tt e rn s o f that s ub gro up ' s food and water consumption, and activities 

### in and around the home that in vo lve pesticide u se in a residential se rtin g . Extensive data on food consumption pattern s are comp il ed by the U.S. Department of Agricu ltur e und e r the National Health and Nutrition Ex aminati o n Survey, '· What We Eat in America,'' 

### (N JlANES / WWEIA). T h ese food consumpt io n p attern s a re u se d in pesticide risk assessments fo r a ll registe red foo d u ses of a pes ti c ide. T hese data are analyzed a nd categorized
Pa ge 6of 1 9Nicarbazin Draft Risk Assessment DP No. D427303 by subgroups based on age , season of the year , ethnic group , and region of the country. Additionally, OPP is able to assess dietary exposure to smaller , specialized subgroups , and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children, youths , and adults entering or playing on treated areas post
- application are evaluated. Further considerat ions are currently in development , as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary pattern s among specific subgroups. 4.0 Hazard Characterization and Dose-Response Assessment The toxicology database for nicarbazin is sufficient for assessing risk (See Append ix A). In it s prev ious registration, three non-guideline toxicity studies on a 3: 1 mixture of DNC to HOP (chronic dog, chronic rat , and two-generation reproduction) and one non-guideline study on nicarbazin (developmental rat) were submitted to the Agency. A metabolism study and mutagenicity battery are also avai l able. Since that time , additional studies have been identified as part of a 2010 European Food Safety Authority (EFSA) eva lu ation for the use ofnicarbazin as a feed additive for chickens including: a 90-day oral toxicity study on nicarbazin; a 90-day oral toxicity study on DNC; and a developmental toxicity study in rabbits on nicarbazin (EFSA , 2010). Although the current 40 CFR Part 158 Toxicology Data Requirements include a 90-day oral, 90

- day dermal , subchron i c inhalation, developmental rabbit , neurotoxicity (ac ute and subchronic), and immunotoxicity studies , these studies were not subm i tted for nicarbazin. However , based on a weight-of-evidence (WOE) approach , using all hazard and exposure in format ion avail ab l e to the Agency and conta in ed w ithin the EFSA evaluation , the Hazard and Science Policy Council (HASPOC) determined these studies are not required to support the reg istered uses of nicarbazin (Bever , R , I 0 / 21 / 2015; TXR # 0057261 ). Additionally , an acute dermal toxic i ty study is also required per 40 CFR Part 158 , but is not needed for Registration Review (persona l communication with John Redden , Registration Division , 12/ 2 / 15). No clear target organ could be identified fo ll owing exposure to nicarbazin in the current toxicity database. Decreased body weight was id entified in both the 90-day ora l study and developmental toxicity stud ies in rats. Additionally , fo ll owing 90 days of exposure , effects included: decreases in body weights , erythrocytes , hemoglobin , and hematocrit; increases in blood urea nitrogen and plasma creatinine; increases in severa l re lat ive organ weights; and tubular degeneration in the kidney and degeneration in the seminiferous tubu le. Based on the available data, while all effects at 90 days appear to be of minimal sever ity, an increase in toxicity over time i s suggested when comparing the 90-day and developmental stud i es in rats. In rabbits , lobulation of the liver was observed in the maternal an im als. However , due to low incidence and absence of corresponding effects, the toxicological sign i ficance of this effect is unclear. No effects were observed in studies using the 3 : 1 mixture of DNC to HOP or using DNC a lone including: the chronic ora l toxicity studies w ith a NOAEL of 400 mg/ kg in both dogs and rats ;

Pa g e 7 of 19N ic a rbazin Draft Risk Assessment DP No. 0 427303 th e rep rod uctiv e toxicity s tud y wi th no parental or r e pro du c ti ve effects observed up the highes t dose tes t e d o f 400 m g/kg/ day in rats ; and the 90-day o ra l gavage s tud y with DNC showing no effec t s up to 709 mg/kg/da y i n rats. Therefore , ba sed o n th e ava i lab le data , nicarbazin appears to be more tox ic th an both D NC alone and the 3: I D NC to HOP m ixt ure . In developmental to xicity studies , no de ve lopment a l tox icity was observed in the rabbit. In rat s . decreased fetal we ig ht s were observed in th e pre se nce of m ate rn a l toxicity ( decreased bod y we ig ht s in dams). Th e r efo re, there is no concern for pre -n ata l s u scep tibilit y . T he ava il ab le s tudi es did not ind icate any concerns for n e urot ox ic i ty o r immunotoxicity. Ca r c ino ge n ici ty s tudie s are not req u ired fo r a non-food u se c he m ical. No ev i de nce of mut age ni c ity was observed. N icarbazi n h as low acute tox ic ity (Catego r y 

### T V) , is a m oderate eye ir ritant (Category ( Ill), a nd is not a d e rma l irritant (Catego ry IV) or se n sitizer. The LOA EL o f 181 m g/kg/da y from the 90-da y toxi c ity s tud y is co n s i dered appropriate fo r assess in g ri s k fo r all exposure scenarios. A I Ox d a ta b ase unc e rtainty factor was applied for a

O AEL to LOAEL extrapolation. Howe ve r , it s ho uld b e no t ed that this L OAEL is deri ved from the EfSA eva luati o n a nd doe s not reflect current Agency p o li cy, and th e refore, may be co n s idered to be co n servative. Fo r a ll expos ure sce narios , a 1000-fold 

### UF ( lOX fo r inte rs p ec ies ext r a p o la ti on, I OX fo r intraspec ies va riati on . and !OX 

### UF db) was app l ied . N ic arb az in i s a non-fo od us e chem ical with no res id e ntial u ses and exposure to childr e n is not ex p ecte d ; th e r efo r e, Foo d Quality Protect ion Ac t (F QPA ) safe ty factor considerat ions do not apply.

T a bl e 4
. 1 Ni c a r b az in : S umma ry o f Toxi c olo g ical D oses a nd Endp o int s fo r N on - O c cup a t io nal Hum a n H e alth Ri s k A ssess me nts. L eve l o f Ex p os ur e P o int o f Un c ert a inty Co n ce rn for S tud y a nd T ox icolo g ical Eff ec ts Sce nari o D e parture Fa ct o r s Ri s k A ssess me nts Dermal S ho rt
- LOAEL = 18 1 UFA= 10 LOC fo r M OE = 90 -Dav Oral Toxicitv Term( ! to30 m g/

kg/ day UF11= 10 1000 (EFS/\ 20 I0) days), UF db = 10 LOAEI. = 18 1 m g/kg/day based on Intermediate Te rm ( l 10 6 momhs), decreases in body weights. erythrocytes. hemoglobin. and and Long Tenn hcmatocrit. Increases in blood urea ( > 6 monlhs) nitrogen and plasma creatinine
. Increases in seve ral relative organ \\eights. Tubular degeneration in the kidney and degeneration in the semini ferous tubule. No NOAEL wa;; idem ified. Inhalation Short- LOAEL = 181 UFA = 10 LOC for MOE = 90-Day Oral Toxicitv Tenn (I to 30 mg/kg/day UFH = 10 10 00 (EFSA 20 1 0) day s). UF db = 10 Int e rm ed iat e Te rm P age 8 o r 19

### Nicarbazin Draft Ri s k Assessmen t 

### DP No. 04 27303

T a ble 4.1 N ica r ba z i n: Summary of To x icolog i ca l Do ses and Endpoints fo r No n -Occ u pationa l Human Hea l t h Ri s k Assessments
. Leve l of Ex po s u re Point of U ncertainty Concern for Study a nd To x ico l og i ca l E ffect s Scenario D e parture Factors R i s k Assessments ( I to 6 month s), LOA EL= 181 mg/kg/day based on a nd Long Te rm decreases in bod y weights
. ( > 6 month s) erythrocytes
. hem og l obin. a nd h c matocrit. Incre ases in blood u rea nitrogen and plasma ereatinine. In c reases in seve ral r e lat ive o rgan weigh ts. Tub ul ar degeneration in the kidney an d degeneratio n in the se minif c r

o u s tubu l e. No NOAE L was id e ntifi ed. Point of Departure ( POD )= A data poi nt o r an est im ated point that i s der ived from obse rv ed dose-re s pon se data and u se d to mark the begi nning of extrapo lat i on t o determine ri s k assoc i ated w ith low e r e nviro nm e nt a lly r e l

evan t h uman expos ure s. NOAEL = no observed adverse effect leve l. LOA EL = l owest o b s erved adverse effect le ve l. UF = u nc ertain ty factor. UFA= ex tra po lati on from an im a l to h um a n ( int ers pecies). UFH = po te ntial variati o n in sensit ivity amon g members of the human popu l ation ( intras pecie s). UF db = NOA EL to LOAEL extrapolation. MOE = margin o f expos ure . LO C = level of concern. N //\ = not a pp lic ab le. 

### 5.0 E ndocrine Disruptor Screening Program As req uired by the Federal In sect ic id e, Fungicide , and Rodenticid e Act (FIFRA) and the Federal Food , Dru g , and Cosmetic Act (FFDCA) , E PA revi ews num erous studi es to assess potential adverse o utcome s from exposure to chemicals. Co ll ec tiv e ly, these stu die s includ e acute, subchronic , and chronic toxicity , includin g assessmen t s of carci nogenici t y , neu r o tox icit y, developmental , reproductive , a nd general or system ic toxicity
. T h ese studies incl ude endpoints which may be s u sce ptibl e to endocrine i nfluence, i ncluding effects on e ndocrine targe t organ hi s topathology, organ we i g ht s, estru s cyclic i ty , sex ual maturat ion , fert ility, preg nanc y rate s, reproductive loss , a nd sex rati os in offsp rin g. Fo r eco log ical ha za rd a ss essments, EPA evaluates acute tes ts and chronic studies that assess growth , deve l opmental and r e productiv e effects in diff erent taxonomi c gro up s. As part of its reregistrati on decision for nicarbazin , EPA reviewed these data and se l ected the most sensitive endpoints fo r relevant ri s k assessment scenarios from the exis tin g haz ard databa se . However , as re quire d by FFDCA sec ti on 

### 408(p) , nicarb az in is s ubject to the e nd oc ri ne scree nin g part of the E ndocrin e Di s ruptor Sc ree nin g Program (E DSP )
. EP A has develop e d the E D S P to determin e w hether certa in substances ( including pesticide active and other ingredients) may have an effect in hum ans or wildl ife s imil ar to an effec t produced b y a " naturall y occ urring estrogen, or other s uch endocri n e effects as the A dmini s trator may designate ." The E DSP employs a two-tiered approach to ma kin g the statuto ril y requ ired de term in ati ons. T ie r 1 consists of a battery of 11 sc ree nin g assays to id e ntify the potential of a chemical s ub stance to interact with the estroge n , androgen , o r thyroid (E, A , or T) hormona l syste ms . C he mi cals that go throu gh Tier I scree nin g and are fou nd t o have th e potenti al to interact with E, A , or T hormon a l systems wi ll proceed to the next stage of the E D S P where EPA wi ll determine w hich , if any , of the Tier 2 tests are necessary based on th e available data. T ie r 2 te s tin g i s des i g n ed to id e nti fy any adverse e nd ocrine- r e l ated effects caused by th e s ub s tance , and estab li s h a dose

- respo n se relationship betwee n the do s e and th e E, A , or T effect.

Pa ge 9of 19

### Nicarbazin Draft R isk Assessment DP No. D427303

U nd e r FFDCA sect ion 408(p), the Age ncy mu st screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide acti ve ingred ien t s and 9 in ert ingredients. A second list of chemicals identified fo r EDS P sc reening was publi s hed on June 14, 2013 1 and includes some p est icid es sc heduled for registration review and chemicals found in water. Ne i ther of these lists s hould be construed as a list of known or likely endocrine disruptors. For further information on the status of the EDSP, the policie s and procedures , the lists of chemica ls, future li sts, the test g ui de lin es and the T ier 1 sc ree ni ng battery , please v is i t our webs ite . 2 

### 6.0 Dietary E xpo s ure and Risk Asses s ment N icarbazin is not registered for use in or on a nd food o r feed crops, and t houg h contamination of water bodie s is possib le from target animal feces , t he l imited and targeted use of t he s in g le regi s tered product does not warrant estimation of concentrations in dri nking water ; therefore, a dietary expos ure assessment is not applicable. 

### 7
. 0 R es id e nti a l (No n - O c cupational) Expo s ure/Ri s k C h a r a cteriz a tion The product i s labe led fo r use onl y on the roof s or p aved s urface s of and around commercial s tructures and buildings ; consumer / residentia l applicator exposure is not expected. Addit io n ally. because th e label specifies use in secured areas of l imite d public access and directs applicators to obse r ve the pi geo n feeding and remove excess bait after each feeding, exposures to adults or ch i ldre n fo ll owing applications are likewise not expected. 

### 8.0 Non

- Occupational B y stander Po s t-Application Inhalation E xpo s ure and Risk E s timates Vo lat ili za t ion of pest ic ides m ay be a sou rce of post-app li cat io n in h a lati on expos ure to i nd i v idua ls nea rby pestic i de app li cati o n s. Th e agency so ug ht expert advice and i np ut on i ss ues re lated to vo latilizat i on of pestic ides from its Federa l Insecticide , Fung ic ide , and Rodenticide Act Scientific Advisory Panel (SAP) in D ecembe r 2009, and received the SA P 's final r eport on March 2, 2010 ( http : l/w\\ r w . regulations
. !!ov /# !documcntDetail:D = E PA

- HQ

- OPP

- 2009-0687- 0037 ). Th e agency ha s evaluated the SAP report and ha s deve lop e d a Volatilization Screening Too l and a s ub se quent Volatilization Screening Analysis ( http: //www.regulations.gov/# !docketD etail; D =E PA- H Q-O P P- 20 14-02 19 )
. Durin g Reg is trat ion Review , the Agency will utilize thi s analysis to detem1ine if data (i
. e . , flux s tudi es) o r furth e r ana l ysis are required for nicarbaz in.

1 Sec hnp :// www.rcgulations.gov/#!do cumentDetail ; D=EPA-HQ-OPPT-2009-0477-0074 for the final second lis t of chemicals**~** hnp: // www2.epa.gov / endocrine-disruption / endocr ine - disruptor- sc rccnin g- pro gra rn-ed s p- overview Page 10 of 19

### Nicarbazin Draft Risk Assessment DP No. 0427303 9.0 Non-Occupational Spray Drift Exposure and Risk Estimates Off-target movement of pestic id es can occ ur via many types of pathways and it is gove rn e d by a variety of facto r s. Sp r ays that are released and do not deposit in the app li ca ti on a rea end up offtarget and can lead to exposures to those it may directly con tact. They can also deposit o n surfaces where contact with residues can eventua ll y lead to indirect expos ures (e
. g . , ch il dren play ing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated u s in g drift mode li ng coupled with meth ods employed for residential risk assessments for turf products. Because nicarbazin i s both a granu le and appl ied by hand or h and

- operated equ ipme nt , exposure via drift is unlikely to occur. 10 . 0 Aggregate Exposure/Risk Characterization In accordance w ith the FQPA , HED must consider all routes of exposure , includin g from no npestic idal sources , to est im ate aggrega t e exposu re (i
. e. , dietary (food and/ or drinking wate r) p lu s non-dietary/residential). N icarbaz in is a vete rin a r y drug approved by the FDA with a tolerance of 4 ppm in uncooked chicken muscle , sk in , li ver a nd kidney
. S uch a u se might be applicab l e to an aggregate exposure assessment, however, it is not registered as a pesticide for use in or on and food or feed crops, and the limi ted an d targeted use of the single registered pesticide prod uct does not warrant est im ation of concentrations in drinking water. Ad diti o na ll y , because the product is registered for use in commercial/ indu strial sites and the labe l all ows use only in secured areas of limited public access, neither consumer /residential app li cato r exposure nor exposures to adults or children followi ng app li ca ti ons are expected
. Given that no dietary and/ or non - d i etary/residential exposures are expec ted from its pesticidal uses , an aggregate exposure assessment is not applicable. 11.0 Cumulative Exposure!Risk Characterization Unlike othe r pest ic id es for wh ich EPA has followed a cumulative risk approach base d o n a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to nicarbazin and any other substances , and nicarbazin does not appear to produce a toxic metabo li te produced by other s ub stances. Fo r the purposes of this ri sk assess me nt , therefore , EPA has not assumed that nicarbazin has a common mechanism of tox i c i ty with other substances. For information regard in g EP A's efforts to determine whic h c hemica l s have a common mechanism of toxicity and to evaluate the cumulative effects of such c hemi cals , see the policy statements released by EP A' s Office of Pesticide P rograms concerning common mechanism determin ati ons and procedures for cumulating effects from substances fo und to have a common mechanism on EPA ' s webs ite at http :// www . epa . gov/ pesticides/ c umu lati ve/
. 12 . 0 Occupati ona l Exposure/Risk Characterization As a granulefbait pigeon contraceptive used on paved / concrete areas or rooftops of of fi ce parks , malls , hospitals, sc h ools , bridges , airports , ot her commercial/ind us tri a l buildings/ structures,
Pa ge 11 of 19

### N i ca rb az in Draft Risk Assessment DP No
. D427303 dermal and inhalation exposures to nicarb az in are anticipated for individuals who load , apply , and remove any excess/ un eaten bait. After application and bait removal , post-application exposure is not expected because residues on concrete / paved areas are expected to be limited , nor are any worker activities in areas previously treated with nicarbazin expected that would involve significant hand or body contact with any residues. 

### 12. 1 Occup a ti o n a l H a ndl er Expos ur e/Ris k Es tim ates HED uses the term handlers to desc rib e those indiv idua ls who are involved in the pesticide application process . HED be l ieves that there are distinct job functions or task s related to applications and exposures can vary depending on th e specifics of eac h task
. Job requirement s (amoun t of chemical used in each application) , the kinds of equipment u sed, the target being treated , and the lev e l of protection u sed by a handler can cause exposure levels to differ in a manner specific to eac h application eve nt. The quantitative exposure/ risk assessment developed for occupational handlers of nicarbaz in is based on applications of granules by hand or with hand-operated equipment such as a belly grinder or rotary spreader and , as specified on the label , removal of any excess / uneaten bait after eac h feeding. Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basi s for completing th e occupational handler ri sk assessments. Each assumption and factor i s detailed below on an individua l basis. For more detai ls, see the HED occupational and residential exposure assessment (Crowley, 2015

- 0429981). 

### App li cation Rate and Amoun t of Product Handl ed: As outlined in Table 3.3
. l , the application rate used in this assessment is based on the product label spec if y in g a maximum rate of 1 ounce of product per 5 pigeons
. Applying 0.5% nicarbazin will result in an application rate of approximately 0
. 0000625 lb ai per pigeon. For the purpo ses of risk assessment it is assumed that an entire single product (i.e., a 30 lb bag) is used per da y, or approximately 0.15 lb nicarbazin
. This wou ld treat approximate ly 2,400 p igeons. 

### U

nit Exposu res: It is the policy of HED to use the best ava il able data to assess handler exposure. Sources of generic handler data , used as surrogate data in the absence of chemical-specific data , include PH E D 1.1 and the ORETF database. Some of these data are proprietary (e
. g. , ORETF data) and s ubject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as " unit expos ures" , are o utlined in the "Occ upational P estic id e Handler Unit Exposure Surrogate Referenc e Table 3 ",

3 Available: http: // www2.epa.gov / s it es/ production/file s/ 20 1 5-09/ docum e nt s/handle r-e xposu re-tab le - 20 15
. pdf

Page 12of19N icarba z in 

### Draft Risk Assessment DP 

### No. 0427303 which , along with additional information on HED policy on use of surrogate data , including descriptions of the variou s sources, can be found at the Agency website 4

. 

### Exposure Duration: HED typically classifies exposu r es from 1 to 30 days as s hort-term and exposures 30 days to six months as intermediate-term. Exposure duration is determined by many things , includin g the exposed population , the use s ite, the pest pressure triggering the use of the pesticide , and the cultural practices surround ing that us e site
. For most agricultural uses , it is reasonable to believe that occupational handlers will not apply the same chemical eve ry day for more than a onemonth time frame ; however , th ere may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e
. g . , completing multiple applications for multiple clients within a region)
. Thus , both short- and intermediate-term exposures are anticipated for nicarbazin; lon g-term expos ure s are not expected
. 

### Mitigation/Personal Protective Equipment: The nicarbazin label requires a lon g-s l eeved s hirt , long pants , s hoes , socks and gloves. For the purposes of risk assessme nt , the gloves are assumed to be chem ical-resistant , although , per standard HED practice , risk estimates are also provided at baseline work attire (i.e., no chem icalresistant g lo ves or other PPE). Inha lation expos ure is assessed assuming no respiratory protection
. Occupational Handler No n- Canc er Exposure and Ri sk Est imate Equat ion s For the algorithms used to esti mate non-cancer expos ure and dose for occupational handlers see Crowley , 2015 (0429981). The standard body weight for the genera l population (80 kg) was u sed for all exposure scenarios covered in this risk assessment since the endpo int s selected were not developmenta l and/or fetal effects. Combining Exposures/Risk Estimates Dermal and inhalation risk estimates were co mbined in thi s assessment , since the toxicological effects for these exposure routes were similar. Dermal and inhalation ri sk est imates were combined using the following formula: Tola/ MOE = Point of Departure (m g /kg /day) 7 Combin ed D er mal + Inhalation dose (mg / kg/day) 

### Summary of Occupational Handler Non-Cancer Exposu re and Risk Estimates Based on the label-required work attire and PP E, and the assumption that the required gloves are chemical-resistant, no risk estimates of concern from combined dermal and inhalation exposure were id entified (i.e
. , all MOEs are 2'.. 

### 1000).

4 A vai lab l e: http: / / www2.epa.gov/ pesticide-science-and-assessing-pe s ticide

- risks/occupat ion a l-p esticid e -hand lerexposure-data Page 13of19N i carbaz i n Draft Risk Assessment 

### D P No. 0427303
T able 12.1.1 presen t s detailed exposure and risk calcu la ti ons. 

# F 12
. 1. 1. S u mm a r )'. o f O cc u o a t io n a l H a n d le r Ri s k E s tim ates fo r Ni carb az in 

## - -
-- 

### I De r ma l Inh alati on Co mbin ed Amount Uni t Exposu r e 

## ' MOE5 Exposure Equ ipment App R ate 1 H andled/A r ea _ (ug/ lb ai) 3 Dose (mg/kg/day) 4 Un it Dose (LOC = 1000) Scenario Exposure Treated 2 SL/NG SL/G S L /NG 

# I SL/G (ug/lb ai) 3 (mg/kg/day) 4 SL/NG/ SL/G/NR 

### NR H

and I 

# I 

# I Loadin g I dispersal 104000 7 1000 0.195 0.134 470 0.00088 930 1.400 applying I I -

## 10,.lof Belly 0.0000625 2400 pigeons 10000 9300 0.0 1 88 0.0175 62 0.00012 9,500 9.900 nulc s to g rinder

_ l b ai /pi gco n (entire 30 lb paved bag) 

### -- - o ncrctc R o t

ary 440 240 0.000 8 3 0.00045 1 0 0.0000 1 9 220,000 380,000 areas sp r eader

·- I Based o n r egistered label on re gistered label s o uilincd in Table 3
. 3
. 1
. 2 Exposure Science Advisory Counci l P o licy #9
. 1 and infom1ation provided on label s 3 13ased o n the ··o ccupational Pesticide I landler Unit Expo s ure Surrogate Reference Table" " (September 20 I5 ). SL = si n g le la ye r ( lo n g-s lec\le s hin. pants . shoes / soc k s NG = no gloves
. G = glO\ cs . N

R = n o**c~pirator .**  4 Dcrma l/ lnlmlau o n Dose = Un i t Exposure ( 11 gf lb a1) • Co nversi o n Factor (O.O Ol m gf11g) • Applicati on Rate ' Arca**Treated ~**  100°0 abso rpti on + BW ( kg )
. S Combmed MO E = POD ( mg/k g/ day ) + [Derm al Dose ( mg/k g/ day + Inhalation Do se (m g/ k g/

dar) J

Page 14of 19

### 12 .2 Occupati onal Post-application Exposure/Risk Estimates HED uses the tem1 post-application to describe expos ures that occ ur w he n indi v idu a ls are present in an enviro nm e nt that ha s been prev io u s ly treated w ith a pestic i de (al so referred to as re entry expos ure)
. S uch expos ures may occur w h en worke rs e nter previously treated areas to perform job func tion s, includ in g acti v itie s re lated to crop production , s uch as sco uting for pests or harvestin g . P ost-app li cat io n expos ure l evels vary over time a nd depend on s uch things as th e type of act iv ity, the n ature of the crop or target that was treated, th e type of pestic id e applicat ion , and the c he mi cal 's degradation properti es . In addition , the timin g of pesticide applications , relative to h arvest activ i ties, can gr eatl y reduce th e potential fo r po st
- application ex po s ure. Give n the u ses of ni carbazi n , after app l ication and bait removal , occupational post
- app lic a ti o n exposure i s not expected because residues on concrete / paved areas are expec ted to b e limited , nor are a ny worke r activ iti es expec ted that wou ld inv olve sig nifican t hand or body contact w ith any residues
. Therefore , any applicab le restricted-entry intervals (RE l s) fo r nic arb az in wo ul d default to technical grade acti ve in g re di ent ac ut e toxic ity-based re quir eme nt s . 

### 13.0 Public Health and Pesticide Epidemiology Data B oth the OPP In cident Data System (IDS) and the Centers fo r Di sease Control and Prevention/National In st itute for Occ upati o nal Safety and He a lth (C D C/N IOSH) Sentinel Event Noti fication System for Occupational Ri sk- P est icid es (SENSOR) databases were consulted fo r pestic id e inc id ent d ata on nicarbazin. The purpose of th e d atabase search is to identif y potential patterns in the frequency and sever it y of the health effects attributed to nic arb azi n exposu re . Nicarbaz in i s not includ ed i n th e Agric ultural Health S tud y (A H S), and th erefore does not prov id e add iti o n al incid e nt informat ion . For the Main ID S, from Ja nuary 1 , 2010 to February 4, 2015, th e re were no incident s r epo r ted involving nicarbazin . In Aggregate ID S, from January 1 , 20 I 0 to February 4 , 2 015, there were 3 incidents reported in volv in g nic arbazin. These incidents were classifie d as minor seve ri ty . Overall , there are few incidents reported to ID S in vo lvin g ni carbaz i n . The review of SENSO RPesticides 1 998-20 11 id e ntifi ed no cases involv ing nicarbazin. Based on the low freq ue nc y and seve rit y of incid ent cases reported for ni carbaz in in both ID S and SENSOR-Pest ic id es there does n o t appear to be a concern at this time that wou ld warrant further i nvestigat i o n. Th e Age ncy w ill continue to monitor the incident infonnation and if a concern is triggered , add i tional analysis w ill b e included in the r isk assess m e nt. 

### 14.0 References 14.1 HED Memoranda HED Memoranda Rele va nt to Re g is trati o n R ev ie w . Author Barcode Date Title M. Crowley 0429981 I O

-Nov -2 0 15 Nicarbazin. Occupati o nal and R es id en ti al Exposu re and Risk Assessment for Re gistration Review. E. Evans and S
. Recore 0427460 26-May-20 15 Niearbazin: Tie r I R eview of Human In cident sNicarbazin Draft Risk Assessment OP No
. 042730 3
HED Memoranda Re l evant to Registration Review. A uth o r Bar code Date Titl e R. Beve r TXR# 005726 1 2 l- Oct

- 20 15 N icarbaz i n: Summary of H azard and Sc ience Policy Council (HASPOC) Meeting of September 1 7. 20 1 5: Recommendation s on th e requirement fo r a 90-day oral, 90 -d ay dermal toxicity s tudy , s ubchronic inh alat ion toxicity study
. developme nt al rabb it s tud y. neurotoxicity batte ry (acute and sub chronic s tudies). and an immunotoxicit y s tud y 14 . 2 Publi s hed Literature and Othe r Docum ents European Food Safety (EFSA) Journal (20 10)
. Scientific Opinion on the safety and efficacy of Koffo gr a n ( nicarbazi n) as a feed a dditive for chicke n s for fatteni n g . 8 (3) : 1 55 1
. U
. S
. E P A (2005)
. Pesticide Fact S h eet: Nicarbazin. Office of Preven t ion, P esticid es , a nd Toxic Substances (750 I C)
.

Page 16 of 19

### Nicarbazin 

### Draft Risk Assessment DP No. D427303
A pp e ndi x A: Toxicity Profile and E xecutive Summaries A .l Toxicology Data Require ment s Study requirements (40 CFR 158.340) for nicarbazin are presented below. Use of the new guide lin e numbers does not imp l y that the new 

### (1998) guideline protocols were u sed
. T es t Required 870.1100 Acute Ora l Toxicity
...... . ............................................. .. yes 870.1200 Acute D ermal Toxicity
.. . ............................................... yes 870.1300 Acute Inhalation Toxicity
.... . ...... . ... . .. . .......................... yes 870.2400 Primary Eye l1 Titation
..... . .. . .......................................... yes 870.2500 Primary Dermal Irritation
................... . .......... .. ......... .. ... yes 870.2600 Dermal Sensitization
.................................................... . yes 870.3100 Oral Subchronic (rodent)
.. . ......... . .. . .. ............ ... . ............. CR 870.3150 Oral Subchronic (no nrod e nt)
................................. . ....... no 870.3200 28-Day Dermal
.................................... . .................... . .... no 870.3250 90-Day Dermal
................. . .. . ......................................... yes 870.3465 90

- Day Inh a lati o n ..................... .............................. ...... C R 870.3700a Developmental Toxic it y (rodent)
.................................. yes 870.3700b Developmental Toxicity (nonrodent)
.................... . . . ... . . yes 870.3800 Reproduction
..... ............. ................. ........................ . ..... yes 870.4 lOOa Chronic Toxicity ( rodent)
.................................... . ... . ..... no 870.4200a Oncogenicity (rat)
................... . ... ... . ... .. ... . .. .. .. . ..... .. ....... no 870.4200b Oncogenicity (mouse)
................................................... no 870.5100 Mutageniciry

- Ge n e Mu t ation

- bacterial
................ . ... yes 870.5300 Mutagenicity

- Gene Mutation

- mammalian
...... . .. . ... .. yes 870.5375 Mutagenicity

- Structural Chromosomal Aberrat ion s .. yes 870.5395 Mutagenicity

- Other Genotoxic Effects
....................... no 870.5550 Mutag,enicity

- Unscheduled DNA Synthesis no 870.6 1 00a Acute Delayed Neu rotox. (hen)
........................... . ......... CR 870.6200a Acute Neurotox. Scree nin g Battery ( r at)
....... . ..... ...... .... yes 870.6200b 90-Day Neuro. Sc reenin g Battery (rat)
......................... yes 870.6300 Develop. Neuro
............ .. . ...... . ...... .. .. . .. . ... . ..................... CR 870.7485 General Metabolism
................................................ . ... . . yes 870.7600 D ermal Pe n etrati on ................. . ..................................... CR 870.7800 lmmun otoxicity
......................................... . ............. . ..... yes 1Study not required. See h azard id entificatio n / toxicology section for exp lanation s. CR = Cond ition al ly Required

Page 

### 1 7of19 Technical Satisfied yes no 1 yes yes yes yes no 1 no no no 1 no 1 yes no 1 yes yes no no yes yes yes no no no no 1 no 1 no yes no no 1

### Nicarbaz in Draft Risk Assessment

A.2 Toxicity Profil es
Table A.2.1: Acute To x ic i ty Profile for Nica rb azin

G uid e lin e Study Type MR ID #(S) No
. 81-1 Acute Oral [rats] 464164 13

870.1000 81-2 Acute Inha l ation [rats] 464 164 15 870.1200 8 1 -4 Prim a r y Eye Irrit at ion 464164 16 870.2400**[rab~** 

# - - -- 8 1 -5 Prim ary D e rm a l Irritation 464 164 17

870. 2500 [rabbits] 8 1- 6 Dermal Sensitizat ion 464 16418

870.2600 [guinea pigs]

- T a bl e A.2
. 2: Toxicolo!!v Profile T ab le: N icarbazin Type o f St ud y Titl e stud y/ G ui de lin e 8 2 -l a 90-Day Oral Tox icity , Rat 870.3100 NI A 90

- D ay oral toxicity, Rat N icarb azin

NI A 90-Day ora l toxicity, Rat DNC 82-2 90- D ay Derm a l 870.3200 870.3465 90- d ay Inh a l at ion 83

- 3a Developmental t ox icity, Rat 8 70.3700a Acce pt ab le/Non-G uid e lin e 3:1 D NC: HDP

83-3b Developmental toxicity. Rabb it 870.3700b j N icarb az in MRID
NI A EFSA 20 10

EFSA 2010 NA NA 46416421

EFSA 20 10 

### DP N o . D4273 03

Re s ult s To x ici ty Ca t ego r y LDs o > I0,000 mg/kg IV

LC so > 0
. 147 mg/L IV Moderate Irr itant Ill

Non- Irritant IV Not a se n s iti ze r 

## I I

Re s ults/ Co mm e nt s
H ED detennined that t he stud y is not req uired. NOA EL n ot d e te rmin ed LOA EL= 181 mg/kg/day, based on d ecreases in body weights , e rythr ocytes, he m oglobin, and h ematocrit. Increases in blo od urea nitrogen and plasma creatinin e . In c reases in severa l relative organ we ig ht s. T ubul a r degeneration in the kidney an d degeneration in the se minif ero u s tubule

- NOA EL = 709 mg/kg/day No effects were id e ntifi ed. HED d ete 1mined that th e s tud y is not requ ired. H ED determined that the study is n ot req uired
. M at ern a l NOA EL = 200 mg/ kg/day Maternal LOA E L 

### = 600 mg/k g/day based on Decreased body weight in dams Developmental NOAEL = 200 mg/kg/day , developmenta l toxicity was not noted at the d ose le vels tested.
Mate rn a l NOAE L : 60 mg/kg/day


### Page 18 of 19

### Nicarbazin Draft Ri sk Assessmen t DP No
. D427303
Tab le A.2.2: To x ico lo!?.V Profil e Tab le: N i ca rbaz i n

Type of Stud y T i tle MR ID Res u lts/ Co m m e nts s t ud y/ Guidel i ne Maternal LOAEL: 120 mg/kg/day based on lo bu lat ion of the Ii ver. Developmental NOA EL: > 120 mg/kg/day 83

-4 Reproduction (2-generatio n) , Rat 46416422 NOAEL > 400 mg/kg/day 870.3800 Acceptable/Non-Guideline No effects were identified. DNC:HDP 3: I 83-1 a 

### I Chronic feeding , Rat 464 164 19 NOAEL > 400 mg/kg/day 870.41 OOa Acceptable/Non

- Guideli ne No effects were identified. DNC:HDP 3: I 83

- lb C hronic feeding, Dog 464 164 20 NOAE L > 400 mg/kg/day 870.41 OOb Acceptable/Non-Guideline No effects were identified. DN C:HDP 3: I 84-2 

## I Ames mutagenicity 46416423 Negative 870.5100 Acceptable/Non-Guideline 84-2(b) Micronucleus Assay (CD- I Mice) 46416424 Negative 870.5375 Acceptable/Non-Guideline

- 84

-2 DNA Damage ( HI 7Rec and 46416423 Negative 870.5550 M45Rec) Acceptable/ Guide Ii ne 870.6200 Acute Neurotoxicity, Rat NA HED determined that the study is not required. 90 day Feeding Subch ronic NA HED determined that the study is not 870.6200 Neurotoxicityscree nin g battery , Rat required. Metabolism, Rat 4315350 1 Nicarbazin did not appear to be well 85-1 Acceptable/ Guideline absorbed , and was partially metabolized as 870.7485 both metabolites and parent compound were identified**erimar il** **~** in the feces. 870.7800 lmmun otoxic ity NA HED determined that the study is not 

## I required.

Page 

### 19 of19