IR58 78/ t•C Codf 108209 Subc hron i c (90- day ) Oral Toxicity S tudy (Rats) (2<l0l) Page I o f 15 OPPTS 870 .31 00 I OECD 408 EPA P ri ma ry Reviewer: Kelly Schumacher, M
. S. Regi stration Action Branch 2, He alth E ffects Division (750 9C) EPA Secondary Revie wer: Ala n L evy. Ph
. D. Re gistration Action Branch 2, Health E ffects Division (75 09C) 

### TXR#: 0052629 Signature: 

# 141 /4--..c.L-
. Dat e {/;IV 

### c..;- Signature: 

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# ,**~tJ** Date wl u../?
. / g 

### tto./- Tcmpl ar.;;' , ,ersion 1110 I



### DAT A EVALlJATION RECORU STUDY TYP E: 90

- Day Oral Toxici t y Feeding Study- Rats; OPPTS 870.3100 (§82-la) ; OECD 4 0 8. 

### PC COI>E: 108209 DP BARCODE: 0306738 SUBMISSION NO.: 8755326 TEST MATERIAL (PURITY): lR5878 (Ortho su lf amuro n , 98.0%) S YNONYMS: 1

- (

### 4
. 6
- dimethoxypyrimidin

- 2-yl)

- 3

- [2

- (

### dirnethylcarbamoyl) -pheny lsulfamoyl] urea; benzamide , 2-[[[ [ [(4,6-dimethoxy-2- pyrim idinyl )arnino Jcarb onyljaminoj sulf onyl]amino }- .K 

### -N -dimethylCITATION: Webley , 

### L. (200 1)
. IR5878 T ox ic ity study by die tary admi nistratio n to Han Wistar rats for J3 

### weeks followed by 

### a 4 

### week reco very per iod
. Hunt ingdon Life Sciences Ltd, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, England PE28 4HS
. Study 

### No. AGR 128/0 12 174, October 1 6.200 1. 

### MRID 46260 I 

### 03. Unpub lished. SPONSOR: lS AGR O SpA , Centro Uffici San S iro - Fabbric ato D
. ala 3. Via Caldera , 2 1, 20153 Milano- Italy
. E XECUTIVE S U MMARY: In a 90-day subchronic oral toxicity s tudy 

### (MRID 46260 1 03). IR5 878 (98
.0(YI• 

### a.i
. . 

### Batch No. 

### FCFIT/ I72 -00 (ex 20525/03/8) was administered to ten Han Wis tar rats/se xi dose in the di et at do se levels o fO, 250. 1500. and 90 00 ppm 

### (equivalent to 0, 

### 19 , 113. 

### and 706 mg/kg 

### bw/day, respectively, for ma les and to 0, 22, 1 31 , 

### and 773 mglkg bw/day, respectively. 

### for fe males). Concurrently , 

### a rec overy group 

### of fi ve 

### Han Wi star rats/ sex/dose were adm ini s tered 

### either 0 or 9000 ppm (equival ent to 

### 0 or 706 mg/kg bw/day, respec ti ve l y , f or males and 

### to 0 or 

### 773 mg!kg bw/day , respect ively, for females) during the 90-day study period and were then mai ntai ned for an 

### add itional four weeks on the control diet. There were no compound -related 

### effects on mortality, body weights , body weight ga in s, food consumptio n, nl.!uro l o gical o b servations and measurements, hema t<>logy, clinical chemistry, or gross pathology
. Compared to controls, an increase in 

### dorsal hair Joss was seen in fe males, but thi s 

### finding i :-; 

### C• ) mmon. Other 

### treatment-related effects 

### (transient increases in liver weight 

### andIR5878/ PC Cndc 1082 09 Subch ron ic (90-day ) Oral Toxicity St udy ( Ra ts) ( 2001) Page 2 of 15 OPPTS 87 0.3 1 00 I OECD 408 hepatocellular hype rtroph y in high-dose males compared to controls) indicate a minimal, adaptive response in t he liver following exposure to IR5878 that i s not considered adverse. The LOAEL was not identified in this study (>706 mg / kg/day for males and >773 mg/kglday for females). The NOAEL is the highest dose tested in**thi~** study (9000 ppm), which was equivalent to 706 mglkglday for males and 773 mg/kglday for females.

This study is Acceptable/Guideline and satisfies the guideline requirement for a 90-day ora l toxicity study ( ()PPTS 870.3100 ; OECD 408) in the ra t. COMPLIANCE: Signed and dated GLP. Quality Assura n ce, Flagging, and Data Confidentiality st atements were provided. I. MATEfUALS AND METHODS A. MATERIALS: l. Test material: Descripl ion : Lot/Ba td• # : Pur i ty: Compoun d Stability: CAS No. ofT<;AI : Structure :

IR5878 Whi te crys ta lline powtkr Batch No. F CF ff/ 172-00 (c.\ 20525/03 / 8) 98 . 0 o,., a.i . Stahle in rodent diet fiw 15 days m Jfeezing temperature and ti)r 8 day s at ronm temperature 213464·77-8 2. Vehicle and/or oositive control: The test material was incorporated i nto the diet. No positive control was used in t his study. 3. Test animals:**Specie.~:** Strain: Age / weight at study ini ti a tion: Sourn: Bousing: ()iet: Water: Environmental conditions:

t\ cclimation per iod :

Rm l-Inn W1starAppr o x im atel y 37- 41**d:~y$** of age I males : 135-138 g . females: 10 8-112 g ll<trlan UK Lim1 t ed. B i c.:c st c r . Oxfordshire, England Ho us ed live o f the sa me se x per cage in stninlcss steel cagt:s with sta i nl ess stcd mesh

I ids and floors Rilt <Jn d Mouse No. I Maimcnance Diet (S pecial Oiet s S e rvices Lt d .. Wi tha m. Essex ,

f. n gland). ad libilllm . , ap water, "d libitum Temperature: 19-23 "C Humidity: . ( (). 70% A i r changes: , 15 timcs/h r Photoperiod: 12**hr~** darkil2 hrs light I I d ay s 2 \.\1R5878/ P C Cudt> 108209 

### B. STUDY DESI GN: Subth r o ni c (90-day) Oral T oxicity S tud y ( R ats) (200 1) Page 3 of I S OPPTS 870.3 100 I OECD 40 8


### 1. In life dates: S tart : November 20, 2000 End: February 19 -20 .2001 (Main group); 

### March 19,2001 (Recovery group) 

### 2. Animal a ss ignm ent : Animal s were r andomly assigne d to the test gro ups noted in Tab le I
. 

### Three mall!s with body weighl<; at the ext re me ends of the weight ran ge of the other rats and two males with ophthalmic les ions were replaced by five spare mal es from the same batch of animals. , \tlhe end of the regular study
. the recovery groups were held for an additional fo ur weeks, du ring which they w<.·re fed the l:Ontro l diet. 

# I T ABL E 1: S tud y desig n 

# I Tes t group Co ne . in d iet Do se to animal II Male II Female l oom) ov\' Control 0 0 10 10 Low 25 0 f {19)

**~** (22) 10 10 Mid 1500

**c:'( l13**  **)~(**
**13**

**)** 10 1 0 Hi!!h 9000 c! (706 )

**~** l773l 10 10 Reco verv Gr.ouD Contro l 0 {l 5 5 Hi!!h 9000 c! (1061_

**.** (773) 5 5 •Data lron1

**ll~.:** 51 oJ MR!D 46260103. 

### 3. Dose selection rationale: The dose level s were selected based on the results from a four-week o ral toxic ity study in rats (Report No. AGR125 /000095) where dietary administra tio n of up to 12500 ppm resulted in changes in body weight gains. food consumption. hematology, clinical chem istry , and sp leen weights. These cha nges were also seen at 2500 ppm. Because the high dose , 12500 ppm, was consider ed s ufficiently close to the maximum tolerated dose, 9000 ppm was set as the high dose in the 90-day study
. 4
. Diet preparation and analysis: Premix was prepared weekly by m ixing appropriate amounts 

# or tes t s ub s tance with Rat and Mouse No. 1 Main tenance D ie t. Test diet s w ere then prepared wee kl y , three days in advance, by diluting the concent rated premix and were stored frozen. Homogeneity and stability of l R 587 8 in t he fee d , at concentrations of 50 and 12500 ppm , were tested in an earlier study (Report No. AGR 1 27/003821 ); however, the results of this study v.ere not provided in 

### MR TD 46260103. During the 90

- d ay s tudy , samples of treated f(wd 

### from each test gro up were analyzed on weeks 1, 6 , and 12 for act i ve ingredient concentration using a solvent extraction method, followed by reverse phase HPLC analysis with e xtemal calibration. Res ult s: Homo gene ity analysis: Homogene i ty was confirmed at nominal concentratio n s of 50 and 12 500 ppm in an ear lier st udy (Report No. AGR 127/00382 1 ) ; however. t he results of this stuJy were no t repo rted in MRID 46 2 60103.


### 3 

### ./,

.. . •IR5878 / J>C Codl' 108209 SubciJronic (90
- day) Oral Toxicity Study (Rats) (2001) Page 4 of IS OPPTS 870.3100 I OECD 4 0 8 Stability analysis: Stability ofiR5878 in the diet was confirmed for 15 days with freezer

storage and for 8 days with storage at room temperature in a n earl ier study (Report No.

AGR 127/003821); however, results of the stability analysis were not repo rt e d in MRID 46260 I 03. Concentration analysis: Dietary concentra tions were 97-99%, 94#98%, and 92-96% of targ et concentrat ions for the low-, mid-, and high-dose groups, re spec tively. T he analytica l data indi c ated that the variance between nominal and actual dosage to the an im als was acceptable. 5. Statistics: Body weights and orga n weights were t ested for homog eneity of variance using Bartlett's test. l fsignif1ca nt , a Behrens -Fi sher test was used for p ai rwise comparisons; i f not significant. Dunnett's te st was used. Gross pathological and histopathological findings were an aly Led u::oing Fisher's exac t test to compare each t reated group with control s . For clinical pathology data, i f7 5% of the findings (across all treatment groups) were the

sa me munbcr, then a frequency analysis was conducted. Treatment groups were compared using a Mantel tes t and pain-vise Fisher 's Exact tests. If Bartl elt's test was not significant at the 1% level, parametric analysis was conducted. Then. if the .. : F I test was not s igni fican t at the 1% level, Williams ' test was applied. but if it

was significant at that level, Dunnett's test was used.

[f Bartlett ' s test was significant at the 1% level , the data were subjected to tran sfo rmat io n to obtain equality of variance and then tested again using Bartlett's te st If still significant, nonparametri c analysis was applied. Then, if the HI t est was not significant at the 1% level, S h i rle y's tc.:st was applied, but if it was significant at that level, Steel's test was used. C. METHODS:

L Observations: la.**~a~eside** observations: Animals were inspected tw ice a day for signs of toxicity and mortalily . lb. Clinical examinations: Clinical observations were conducted weekly. lc. Neurological**evaluation~:** The following observ ations were made on ten an imal s/group/sex prior to initiation of t he st ud y and weekly during the dosing. period and on a l l of the recovery phase animals in the final week ofthe recovery period: exophthalamos, fur condition , lacrimation , piloerec t ion , reactivity to handling, ease of removal from cage, salivation, vocalization, activity counts, arousal, convulsion,

defecat i on counts, ga iL grooming. palpebral closure, posture, rearing, tremor, twitch ing, and urination . The following m easure ment s were rec orded prior to**~tu dy**  initiation and I; I.J'IR5878 / P C C01l e 108209 Subc h ronic (90-dRy) Ora l Toxicit y Stu dy (Rats) (200 1 ) P ageS of 15 OP PTS 870.3100 I OEC D 408 

### dunn g wee k 12 of the dos i ng perio d for 10 an imals/ g roup/se x and during week 4 of the r cco'.ery period fo r all of the reco vt:ry phase animal s: approach res p onse. audi tory startle 

### re l kx
. b ody temperature , body wei g ht. grip s treng t h , landing foots play, tai l pinch respon s e. pupi l reflex , rightin g refl ex , to uch response, and moto r activ i ty . 2. Body wde llt : Animals were weighed prior to i nitiati on of the study, on t he tirst da y of dosing. weekly during the dos ing and rel:overy p eri ods, and b e fore necropsy. 3
. Foo d co n s umption and co mpound intake: Foo d consumption for each cage was determin ed
. and mean weekly d iet co n sumption was calculated as g food/animal/week. Gro up rn enn f ood efficiencies were calc ul ated on a weekly basis as IOO*(g body wei ght gain pe r weck/g tood co n s umption p er week). Compound intake ( mglk g bw/day) values were calcul ated as t ime-weighted average s from the c o n s umption an d b o dy w eight gain data. 4
. Qn h t h a lmosco pic exa min ati on : Ey e s o f all animal s were exam i ned before dosing (week -1 ) using ind irect ophthalmoscopy. Eyes of a ll s urv iving co nt rol and hi gh

-dose animals were also si mil arl y examined during we ek 13. 

### In both cases , a 0. 5% trop icamide s olution was insti lled prio r to examination. 5. Hematol on a nd clin ical ch em is t ry : After an overnight fas t, bloo d was coJlec ted from the retro-orbital s inu s of all main study animals duri ng week \ 3 and from all recovery study anim als m week 4 of the recovery period
. D uri ng sampling , animals were he ld un de r isotlura nr..: anesthesia. The C HECKED (X ) parame te rs were exam ined.

X 

### a . H e m ato lot::Y: Hcmntoc ri t (I IC T)• H

emogl< • hin t i iG B)* Lcu k CX:;> ll' count (W BC) •

**ryth ;yt~**  count tRRC) *

**la lt:t**  **~:r•u nt**  **•** Alond d oli in g. measu rem ents*

**{Thrc•mbopla.~tin** time) Leu kocyt e d iff erential cou nt • Mean co rp usc ul ar H GB (MCH) * :vtean co rpu sc . 11 G B cun.c . ( M C H C)* Mean co rpu sc . v o lu me (
. \IICV)• R

e ti c ul ocy te co unt

• Recommended' '-" 'JO-day oral roden t stu dies

**ba. d**  on Guideli ne 8 70
. 3 100

- Nl)\

**~xamino.:d**

5Subchronic (90-day) Oral Toxicity Study (Rats} (200 l} Page() of I 5 IR 5 878 / PC Code .**..:.I~08::,:2 ~0~9** **------- --** **------ ----0~P:...PT.:.:S=87.:...:0:.:.:.3::..:** **1..::.00:;:..:... /** **O=E.:::C~0...:4=08** b. Clinical chemistry: Calcitn Albumin* Creatinine • Urea nitrogen• Tolal Cho l csl<!roJ• <llobul i ns Sodiu : n• Glucose* l l- --ll--- l -:N-7- . V-M-r..-·s_(_m_o_r_e-th_ a _n_2_h_e_at_ic-e- . n - z-yr -n-c s -)*'--·tl---il Total bilirubin i \ lka li t lo.:: phosrhatase (ALK)'• Total protein (TPl* Cholin:'l< ' rasc (ChEl Trig.lycerides

OTHER ('n:aii n o.: pl w srhokinasc Serum protein electrophoresis**La ~ti'**  ;,c i d d e h y d rogenase (LO l l) Albumin / globulin nllio /\l a n i tiL ' : uu i nNmnsfcrasc (/\LT / also SGPT)•**Aspart<~ c**  < iiHinotransterase (ASTialso SG(}I)t Sm\>ilul**lkh (\rogenasc~**  Cianuua gl u rarnyllransferasc (GGT) * *Recommended fn r 90-day oral rodent studies based on Goidclinc 870.3100 - :-.lot< : xamin,:d 6.**rinalv ~is** **:** Urine was collected from fasted main study animals during week 13 and fro m fasted n.:.:(.overy phase animals during week 4 of t h e recovery period. The CHECKED (X) paramet ers were exam in ed.

Spe cifi ( gnwny/osmolality* pH* • Recommended l\)r 90-ctay ma\ rodent s \udies based on Guideline &70.3\ 00 - Not examined 7. Sacrifice and pathology: All animals w e re sacrificed by carbon diox id e inha la tion and were subjected to gross p atho lo gical examination; the CHECKED (X) tissues were collected for h istolog ical examina t io n. The head, larynx , n ose , pharynx, sa livary g land (one only) , sc iatic nerve (one only) , and skeletal thigh muscle (o n e on l y) were collected and preserved , but thes.e organs \Wn.: no t exami ned histologically . The (XX) organs, in additio n , were we igh e d . 6IRS878 / PC Ctldc 108209

n rc:F
.STIVIi. SYSTF.M

- Ton!f U O.: X X

**SalivJr~** g. lands• XX X

**Esoplw gus~**  

### - X Stom .;ch "' X X D unJ.:nam• XX X

**lll l!Ul"**  **'~** XX X llcU!r' 

# rx- ( \:ctun• X Co l on• XX X Rect um " X XX Li\O.: I"l
. XX



## - Gall \•l a• hkr• (not rnl) XX


## -

- 13ilc cttll X X f>an cr.:a.- " X l{l:SPIRATORY XX X

**TradJ**

**<~ ·**  XX X Lun!! ' X X N<>s<·' X Pharvn .\ ' X L 'IT\'11' • S u bc h ronic (90·day) Oral T oxicity S tudy (Rats ) (2001) Page 7 o f IS OPPTS 870.3100 I OECO 408 ( "4 RnlOV4S( ./HF.MAT
. J'lEI IROI.OC.:If Aort<\* XX

**Brai11~ +**  lleart• + X P erip heral nc:rw: • Bo nt: marrow* X Spinal cord ( 3 k:\ • c: b) • Lymph node,• X Pitui t ary • Spleen• • X E}es (op tic nerve)" l1lymu s• + CLA N OtJ LAR XX Adrenal gland* + U RO<;ENITAL X Lacrimal g land

**dne y~**  **+** XX r•arath yro iu'" Uri nary bloddt\r• XX T hyroid•


## -

**Testes•**

**·~**

**Epididymidc**

**+** Pros tatc * OTHER Semina l v.:s idcs • X Bone (s ternu m and lemu r)

**Ovnri..:~**
**+** X Skeleta l musch: Ute ru s • ... X Sl..in• Mammary gl1111d • X All gross lc: stons anol n1asses• X 1-lead

• Recommend..: 1: f1 ' r 90 -duy oral r oden t stud aes ha.scd on (Jtudd tn e S70
. 3 100

· l Organ weight, rl'<: u irc d lor rodent s tudil- s

- Not examin.:d

7Subchronic ( 9 0- d ay) Oral T oxicity St ud y ( Ra ts} ( 2001 ) Page 8 of 15 IR5878/ PC**Codc...! .::.:08~2~0** **:...9 ---** **---- ------** **--.;:;O.:.P.:...PTS .:..::::.~87:....::** **0;.:.:: .3:...:.** **1.::.;00::,.; 1...:0::;,;E:::..;C** **=:.:0~40~8** 11. R E SUL TS A.**OBSE~V** A TIONS: 1. Clinical**si~ns** of toxicity: Th e on l y treatment- r elated cl i n ica l sign of toxic ity observed was hair loss from the dorsal body surface, beg in ning on week 1 for bo t h males and females. Hair l oss wa . s fl lun d in 3/10, 2110, a nd 6/ 1 5 o f the low-, mid-, and hig h- dose males. respectively. compared to 0 / 15 o f control males. In**ft~ma le** **s,** 4/10, 4 / 10 , and 12/15 animals were affected in the low- . mid-, and high-dose gro up s, respectively, compared to 2/ 1 5 of control fema l es . Although no hair loss was seen in control and hi gh-dose males during the recovery period. 215 of the**~:onlro l**  females and 5/5 of the high-do se females also exhib i ted hair loss during the four week recovery phase. 2. Mortali ty : N o trea t ment-re l a t ed mortalitie s occurred during the study. One contro l female h ad overg rown and maloccluded t eeth and was sa cr ificed during week four for hu mane reasons. 3. Neurological eva luations: Mean fo r elimb gr i p s t r ength values were lo wer in all treated males compared t o controls during treatment week 12 . However, no dose -r esponse was observed , a n d none of the differences between treated and contro l males were statis ti cally s i gnificant. Forel i mb grip strength in females and h i ndl i mb grip strength in both males and females were si m ilar to controls at all treatment l evels. A s s ho wn in Table 2, a s t at i stically significant increase i n mea n landing footsp J ay was seen i n**high-dos~~** females compared t o control ft::ma l es in week 4 of th e r ecovery phase. P ri or to tr e atmem, no difference in mean l anding footsp l ay between ten control and te n high -dose females wa s obser ve d . Howeve r, a n examination of the indivi du al data in dic ; ated that th e landing f\)otsplay values for just t hose females that were examined on re co ve ry week 4, in add ition to t r ea t ment weeks 0 and 1 2, d i ffered before t h e in i tiat ion oft h e s tu dy. Specifically,

on t r eatment week 0 , footsp l ay ranged from 42-75 mm in the five control females and from 67-94 mrn in the five high-dose females maintained throughout the recovery p hase of the study. No dif ferences in land i ng footsplay were seen between any of the treated females on treatmem \Veek 12 co mp ared to t h e control femalt:s or between any of the trea ted ma l es compared to cont rol ma l es on treatment week 12 and r ecovery week 4. As shown in Tab le 3 , s tati s t ically sig n ificant decreases were seen i n the number of high -b eam breaks made on treatment week 12 by low- and m i d-dose males compared to controls. However . prior t o the initiation of the study, t he nu m ber of high-beam breaks made by t he these low - · and mid - dose males were a l so lower compared to con t ro l s, although th e diffe r ences we r e not s t at i stically s ignificant. No dose-response was seen; t h e number of high-beam break s made by hig h- dose ma l es did no t differ trom controls. Co m pa r ed to

controls, thl' number of high

- beam breaks made by fema les and t h e n umber oflow-beam

breaks math. · by both males and females were unaffected b y all l evels of treatment.IRS878/ PC Code 108209 Subchro nic (90-day) Oral Toxicity Study (Rats ) (200 l) Pllge 9 of 15 OPPTS 870.3100 I OECD 408 TABLE 2. Mean lllnding foots p l av

_ (mm ::1: SO) in rats fed IR5878 for lJ weeks' ' 

### Males Female s 

### Dos e (ppm) Treat ment Treatment Recovery Treatmen t Treatment Recovery Wee k ()b Week llh Week 4' WeekOb Week 12b Week4 ' 0**~(1** ::1: 13 128 ± II 12 0 :!: 20 7() ::1: 21 106 :!: 17 75 :!: 17 250 91 :1: 21 125 ± 22 NIA 82 :1: II 121 ::1: 14 N / A 1500 81**~25** 123::1: 19 N iA 8 4 ::1: 19 1 17 ± 10 N / A 9000 . 81 :1: 17 133J:I3 125 :.1: I I 81 :1:9 101!± 17 101 ::1: 15
.

·'Data oblamcd ! r om pages 336-33 8 m the**~tudy** report. • n = I 0
. intl ud in g**tho ~c**  5 animals ob se rved al r e covery w c .:k 4 • n = 5 •**Signili~.;an l~** **.llff.: nl**  (rom controls, p•, 0
. 05 Ti\BLJ: : 3. 1\tean moto,. activity (beam b reaks ± SD) over 60 mi n utes in rats fed IR5878 for 13 weeks• Males Oosc( ppm) Treatment Treatment Recovery WeekOb Wee k**12~** Week 4 ' Hi gh beam breaks 0 <JO± 26 1 47 ± 41 161 :t 105 250 58± 35 95 ±J 8
.. N!,'\ 1500 73 r 59 107 ± 30. N /,\ 9000 JO I ±51 125 ± 44 103 ± 36 Low beam b r eaks 0 410± 124 697 ± 180 640 ± 204 250 291 ::1: 159 H6 t . 182 N I A 1500 3 68 ± 12 5 594 ±12 1 N / A 9000 -+5 4 ;; 254 624:!: 248 66 4 ± 83 'Data obtarncd lnm1 pages 3 42

- 346 m tht:**udy** n:pon . 1 ' n = I 0
. indudin g rho :: c 5 animals observe d at recovery week 4 ' n = 5 * Signilkantly dil f crc nt from contro ls. p· · 0
. 05 H Signilicantly**;~, f.:** **.n.m t**  fi·om**control~.** p ; O
. OI Females Treat ment Treatment Recovery

Week Ob Wee k 1 2b Week 4 '

99 :t 45 13 1 :I: 42 Ill .± : 44 83:!: 56 10 7 ± 3 8 NIA 79 :!: 30 99 ± 41 Nit\ 1!3

.:!: 3Y 114 :1: 37 X7 ± 70

358:!:: 1 44 623 ± \30 4 82 :!: 198 358 :t 100 555 ± 1 36 N I A 41 7**~** 1 48 584 ± 161 N/ A 3 76 ± 139 663 ± 17 3 563 ± 32 8 

### I

B. BODY WEIGHT AND WE I GHT G A I N: Mean body weights and to tal body weight gains are g iv e n in Table 4. 

### The r e were 

### no treatment-related e ffects on bo dy wei ght s or body weight ga ins 

### in the main or r ecovery phase s of this st u dy.

9IR5878 / PC**Cod(~** 108209 S ubch ro nic (90-da y) Oral Toxicity Study ( RatsJ (2001) Pa g e 10 of 15 OPPTS 87 0. 31 00 I OECD 408 TABU : 4 . Mean body wel2.hts and bodv wei2.ht 2.ains (SWG) durin!!. 90 days of treatment" D os e Bod y weights (g ::1: SD) BWG (g)

- Bod y weights ( g ± SD ) BWG (g)- (ppm) r--· Trea t m e nt Recovery Wel•kO Week I Week 7 Week 13 Per io d Rerovcry Re c ov e ry Period WeekO Week4 Male 0 I**1~** .I X 175 ± II 318 ± 26 367 . t 32 230 365 ± 26 38 4 l: 23 19 250 J.l( • ± 6 176 ± 9 318 * 29 369 I · )8 233 N l i\ N I A N f i\ 150 0 u . < ! : t 172 : d i 306 .1: 2 1 3 56 ! · 28 221 Nil\ N / 1\ N i l\ 9000 13( > I: 6 1 7 3 -;!: 8 3 1 1 t 28 3 67 ± 40 231 398 ± 53 422 ±5 2 24 Fe m ale 0 101; t. X 12 7 ± 12 188 ± 22 2 11 .1: 22 103 1 96 :l I I 2 0 4 = J () 7 250 I ll I. 6 132 l 10 197 ± 27 221 :1.. 25 I 10 N/ A N i A N I A 1500 I I :: '5 1 3 2 :1: 7 194 ± 1 3 214 : l:o 16 102 l'- I A N/ A N f A 9000 Ill :f 6 133 ± 8 196± 16 22 1 !: 1 6 1 0 9 230 ± 17 239 ± 17 9 • Data oh t aincd**f··~ nJ**  pa ges 43-45 in t h <: s tud)' rc: port. C. FEED**ONSUMPTION** AND COMPOUND INTAKE: l. Feed consumption: There we r e no treatment-related effects on food con sump t ion. 2. Compou_nd Intake: Time-weighted average com pound intak es are shown in Table 1. 3. Feed Efficiency: Th e re were no t reatment-related effects on f ood efficiency. D. OPHTl(ALMOSCOPIC EXAMINATION: Th ere w ere no tre i\ tment-related ophthalmological fi n d i ngs . E . BLOOD ANALYSES: 1. Hematology: Selected hematology data ar e given in Table 5. Mean red bloo d cell (RBC) counts were m arg ina lly dec re ased in high-do se fe ma les jn the main study comp are d to co ntr ols, but thi s decr e as e (
- 6 %) i s not biolo g ic a ll y m e aningful. Additionally , no significant decreases in me an RBC counts were seen in t he low- or mid-dose main study fema l es , the

high-dos e**~ma le** **s** following a four week reco v ery period, or i n any of the trea ted ma le g roup s. 'Vhite blood cell and lymphoc yt e counts were slig htl y decreased in all treated male a nd f emale gro ups following 13 weeks of tr ea tme n t with IR5878; h owever , t hese paramet e rs were comparable to controls for both males and f emales following a four week re covery period . 10IRS878 / PC Code 108209 Subcbronic (90-day) Oral Toxicity Study (Rats) (2001 ) Page I I of tS OPPTS 870.3100 I OECD 408 TABLE 5. Selected he ma to logy findings in rats fed IR5878 for 13 weeks• Do se Red blood cells White blood cells (ppm) (to·IZJL± SO) (10' 9/ L ±**SD~** Male Main Group -Treatment Week 13 () 8.6 ± 0
. 3 8.5 .± 1.2 250 !! 7 :1: O .J 7
. 0 :1: 1.4 * 1500 t!.5 :t (14 6.9 ± 1.1
.. 9600**6** *- 0 2 6 .7 ± 1.4 

### ** Male Recovery Group· Recov ery Week 4 0 N!A 7
. 6 k 1.7 9000 N/A 7
. 1 t 1.2 female Maio Group- Treatment Week 13 0 7.<) 1:0.4 5
. 5 :1: 1. 0 250 7
. 7 :1: 0.5 4
. 7 ± . 1.2 + 1500 8.0 : \ (1.3 4
. 5 ± 0.6
. 9000 7.4 J: 0.3 * 4.0 t 0
. 6 .. . female Recovery Group- Recovery Week 4 0 7
. 7 ::1: 0
. 3 4 .1 ± l.R 9000 7
.6 ± 0.3 5
. 1 ± 0
. 7

·· Da1a obtamed from pages 55-60 10 the study repo11
.
, ,. Significantly different from controls, p <0.05 ' '' * Significantly difl\!rc n t from controls. p • , 0
.0 l Lymphocytes 00' 9 /L± SD)
6.4 .± 0.9 5
. 4 t: 1.5
.. 5.3 ± 0
. 8 * 4.8 ± 1.1 

### **

5. 7 :l: 1.7 5
. 3:!: 0
. 9
4
. 5:1:0.9 3.6 ± 0.9. 3.4 ± 0
. 5 •• 

### : u 1:0.6 **

3.] ± 1 .2 3
. 9 ± 0
. 7



### 2_ Clinical chemistry: In treated males compared to controls, statistically significant changes were seen in aspartate aminotransferase, ereatine, phosphorous , total protein , albumin, and albumin / globulin**values~** 

### however, none 

### of these changes are considered biological1y significant. Similarly, in treated females compared to controls, statistically significant changes were 

### found in chlorine and phosphorous levels, but neither change was biologically meaningful. F. URINAl ! YSIS: There were no treatment-relate d change s reported. 

### G. SACRIF]CE. AND PATHOLOGY: l. 

### Organ weight: Compared to controls. li ver and kidney weights rel ative to body weights were ma rginally increased in high-dose males following l3 weeks of tre atment, ac; 

### shown in Table 6. liowcver, mal e absolute liver and kidney weights in the main study and male absolute and relative liver and kidney weights following four weeks ofrecovery were all comparabk to controls. Absolute kidney 

### weights in**high~dose** 

### females were margi nal ly increased compared t o 

### controls a lkr t he tour 

### week 

### recovery period
. However, female 

### absol ute and 

### relative liver and IIIRS 878/ PC Ct1de 108209 Subchronic (90 -day) Oral **Toxicit~** St udy

**(Rat~)(2001}** Page l2 of l S OPPTS 870.3 100 I OE CO 408 kidney wctghts in the ma in s tudy , femak relative kidney and liver weight s fo ll owi ng recovery . and female absolute liver weight !:i followi n g recovery wer e a ll comparable to controls . TABLE 6. Absolute and relatin orga n weights in rats fed 1R5878 for 1 3 weeks' O OSt' Body weight Liver Liv e r / body Kidn ey (IHlm} (g) (2) (g/ 10 0) (g) Male Mai n Gro u p
- Treatment Week 1 3 0 369 ± 35 1 22 ± 1 . 6

**::** :t. 0 . 2 2 .0 ± 0.2 2:\0 369 ± 39 12 . 2± u

**.3 ~;**  0.1 2 . 0 j; 0. 2 r- - 1 :\0il 35 6 ± 29 I 1.6 .J: I :1 3.2 1: 0 . 2 1.9±Ct . 2 900 0 35 I ± 2 0 13 . 5 ± 1.1 :> . 9 = 0.2 •• 2.0 ± 0 .1 Male Recov e r y G r oup- R ecovery Wetk 4 II 3 84 1: 29 13.5 ±1.7 3.5 ± 0.2 2.1 ±0. 1 **90~0** 422 t 53 1 3.9 ±1.1 3. 3 i. 0.2 2.2 ± 0.2 Female Main Gn>up- Treatment Week 13 r--- n 2 1 5 :1: 2 h 7.9 .1: 1. 1 3 . 7 ± 0 . 3 U ± U.2 250 222::!: 21\ 8 . 1 l: 1.2 ) . 6 ± 0 . 3 1 . 4 ± 0.2 1 51)(1 2 1 6 ± lt. 8 . 0 ± () . 5 3.7 ± 0.2 1.3 :t () . I <)04)(} 2 16 ± 17 8 . 1 :1: 0 .7 3.7 ± 0. 1 1.4 ± 0 . 2 J <e male **R~co very**  G roup
- R (COve r y Week 4 0 204 ±. I I 6 . 9 :1: 0 .7 3 .-l ±. 0.1 1.3 ::1:: 0 1 9000 234± 14•• 8 . 0 ± 1.2 3.4 ± 0.4 1.5 ± 0 . 1 .. • Data <J nt<uncd frum pages 70-77 m the slu dy rcp c • rt . • Signi i' i .:a l llly different from c0ntrols,

**~O.OS** •• Sig n ific antly different from controls. p < O . O 1

Kidney / body (g/ 100 )

0 . 5 :t 0 . 0 0 . 5 :::: 0 . 0 0 .5 ± ll . O 0.6 ± 0.0 .

0 . 5:1 0 . 0 0.5 .1:0.1

0 . 6 ± ( 1.0 0.6 ± (1,() 0.6 ±O il --

0 .6 ± (} , () 0 . 6 ± 0 . 0 0.6 ± 0. 0 A marginal mcr ease in the adrenal gland a b so lute weights following 1 3 wee k s of dosing oc curred **ml y**  in low-dose (not in mid- or hi g h-do s e) females compared t o contro ls. 2. Gross patho)oi!)': There were no tr eatme nt - r elated gross patholo g y findings. 3. Microscopic

**patholo~:** On treatment week 13 , s light centrilobular hepatocyte hypertrophy was seen in 7 / 1 0 of the high-dose males (Table 7), which correlate s with t h e incre ase seen in relative ltver weights. Hypertrophy was also seen in lllO of the mid-do se males on treatment week 13, but n one was seen in low-d ose or co ntr ol males. No hepatocellular hypertrophy

was observed in females after 13 we e ks or treatment or in males or females after a 4 week recover y period . 1 2IR58 78/ PC

**Co d~**  108209 S ub c hro ni c (90-day) O r a l T oxic ity S tu dy {Rats} (2001) P age 13 of 15 OPPTS 870.3 I 00 I OE.CD 408

TABLE 7. Incidence of ce n trilobular hepatocvle hv er trophy in rats fed JR5878 fo r JJ

**week. ~'**  Dose :Vla le Main Group- Male Recovery Group- Female Main G1·oup

- Female Recovery Grou p (p pm ) Tr eatment Week IJ Recove r y We ek 4 Treatmen t Wet k 1 3
- Re cover y Week 4

0 0 / 10 O i 5 0/10 O i 5 250 0110 N i l\ Oi! O N i l\ 1 500 1 ! 10 N ! /\ 0/1() N //\ 9000 7 1 1 0
.. 0 / 5 0 / 1(1 0/5 .\ Dat a obt mn l!d II vn 1 pages 85 and R9 111 th e study report . *•

**Signifil·antl~** diik l\' rll l r(lll\ controls , pd).OI
III
. DISC (ISS IO N AND C O NC L US IO NS A. INVESTIGATORS' CONCLU SIONS : The study au tho rs concluded that , 

### in Han Wistar rats, die t0. ry exposure to IRS8 78 caused dor sa l hair loss in females, s l ight decreases in female red blood cell counts , hematoc ri t, and hemoglobin values : decreases in male and fem ale white bl ood cel l and lymphocy te counts and in phos phorous levels; changes in male creatinin.:: l:once ntra ti on, triglycer ide levels, a->partate amino-transferase a nd a lkalinephosphatas(: activities, and urine composition ; increased male liver and kidney weights; and 

### an increa se in the incidence of s light centri l ob ul ar hypertrophy of mal e hepatocytes. The investigators found no eviden ce of neurotoxicity. The

**inv~stigators** r eport t hat the effects seen in male l iver (i.e., increased liver weight and hepatoceLlular hypertrophy) were not seen following the four week recovery . The study authors d etermin ed that the NOAEL was 15 00 ppm , which is equivalent to 11 3 mg/kg/day for male ral s and to t3l mg/kg /day for f emale rat s. B
. REVIEW E R 

### COMMENTS : Dietary exposure to 1R5878 i n rat s did no t cause a ny treatment-related effects on mortal ity , body weights, body weight gai n s, food consumption , neurological observations and measureme n ts , hematology , cl inical chem i s try. or gross pat ho log). The stat istically significant increases in the relative kidney w e ights of males and of abso l uh: ki dne y weig hts i n f emales (following r ecovery) are not biologically s ig ni ficant. Dorsa l hair 

### lt>ss in female rat<; is considered 

### a treatment-relate d effect ofiR5878 exposure; however
. hai r loss is a co mmon cl inic a l s ign with unclear toxicol ogical si gnific ance. 

### The tr eatment
- re lated increase in relative liv er weights seen in 

### males administered 

### 9000 ppm 

### is considereJ 

### to be an adapti ve response , because liver weights were comparable to controls following a tom week reco very period. there were no biologically significa nt changes in liver enzymes.

**th~rc** were no gross pathologica l ef fe cts in the liver, a nd th er e were no histopathological e ffects in the liver other th an s light trans ie nt centrilobular hepatocyte hypertroph) 

### 1 3I RS878 I PC Ct>dt· 108209 Subchronic (90- da y) Oral Tox icity Stu d y ( Rat s) ( 2001} Page 14 of IS OPPTS 870.3 1 00 I O EC D 408 T he**LOAl L**  was not identified in this study (>706 mglkg/day for males and >77 3 mg / kglday for females). The N OAEL is tbe highest dose tested in this study (9000 ppm) , which was equivalent to 706 mglkglday for males a nd 773 mg/kglday for females.

This study i s Acceptable / Guideline and satisfies t he gu id eline require m ent fo r a 90 -d ay oral

tox icity s tudy ( OPPTS 87 0.3 1 00; OECD 408) in the rat. C. STUDY DEFIC IE NCIE S: Homogeneity of t h e test compound was con firm ed at nomin al concentrat i ons of 50 and 12500 ppm i n an earlier st ud y (Repor t No . AGR I 27 / 00382 1 ) . While s a mpks o f th e ac tua l p r epared diet use d in MR ID 46260103 were not tested f o r h omogem: it y. t hi s does not inva l idate the study results. l4lR5878 / PC C<odt' I 08209 Subchronic (90-day) Oral To11.icity Study (Mice} (2001) Page I of II OPPTS 870.3100 I OECD 408 EPA Primar-y Reviewer: Kelly Schumacher, M.S. Registration Action Branch 2, Health Effects Division (7509C) EPA Secondary Reviewer: Alan Levy, Ph.D
. Registration Action Branch 2, Health Effects Division (7509C) Signature: 

## .-j:;./L, /.: 

## uc.6=1 ) Date 

### : $jl I**~~;:. H**  S • t 

### '.l. I J 

# £**~** 1gna ure: 

### aJA -<; (. ,**.~** , 

# :21 Date '1'1'faa
. 1**4e>.£~5 Tcmplat~**  version I I ! 0 I
OAT A 

### EVALUATION RECORD STUDY**TYP(~:** 

### 90-Day Oral Tox icity Feedi ng Study-**Mice~** 

### OPPTS 8703100 (§82 -1 a): OECD 408
. 

### PC CODE: 108209 

### DP BARCODE: 0306738 

### SUBMISSION NO.: S755326 

### TEST MATERIAL (PURITY>: IR5878 (Orthosulfamuron, 98
. 0% ) 

### SYNONYMS: 1-(4,6-dimethoxypyrirnidin-2-yl)- 3-l2-( dirnethylcarbamoyl)-phenylsulfamoyl

### J u r

ea: benzamide, 2

- r[[[ [ (4, 6-dimet hoxy-2- pyrimidinyl )amino]carbonyl laminojsulfonyllamino]-N -N-dimethyl

### CITATION: Webley , L (2001). TR5878: Prelim inarytoxicitystudybydietary administration to CD-I mice for 13 weeks. Hunt ingdon Life Sciences Ltd, Woolley Road, Alconbury , Huntingdon, Cambridgeshire. England PE28 4HS
. Study No. AGR 129/012173. August 16 , 200 I. MRID 46260 I 02. Unpublished. 

### SPONSOR: ISAGRO 

### SpA, Centro Uffici San Siro- Fabbricatc· D , ala 3 , Via Caldera, 21. 20153 Milano- I taly. EXECUTIVE SUMMARY: fn a 90-day subchronic oral toxicity study (MRJD 46260102), IR5878**(98.0~;.** 

### a.i ., Batch No. FCF/T/1 

### 72-00 (ex 20525 /0 3/8) was administered to te n CD-I mice/sex/dm; e in the diet at dose levels ofO, 250, 1250, and 6000 ppm (equivalent to 0 , 36 , 187
. and 865 mg/ kg bw / day, respectively, for males and to 0. 47, 228, and I 096 mg/kg bw/day, respectively.**l~>r** 

### kmales). There were no**~ompound-re ated**  

### et'tects on clinical signs, mortality, body weights, clinical chemistry. gro ss pathology, or histopathology. Co mpare d to controls, sl ight decreases in food consumption . MCH. and MCY in high-dose females and slight decreases in the lymphocyte count of hig h-dose males were noted, but these changes were not biologically significant. 

### The LOAEI. was not identified in this study (>865 mglkg/day for male mice and >1096 mg!kg/day for females). 

### The NOAEL is the highest dose tested in this study (6000 ppm), which was cqui'" ·alent to 865 mg/kg/day for male mice and 1096 mglkg/day for females. Dosing in this stu · dy 

### is considered adequate because the highest dose tested is sufficientl y close to the limit dose of I 000 mg/kg/day. 

# (l..

IR58 78/ P(' Code 10820 ? Subcbronic (90-d ay) Oral Toxici ty Study ( Mice ) (2001) Page 2 of I I OPPTS 8 7 0 .3 WO I OECO 408 T h i s st udy is A cceptable/Guideline and satisfies the gu ide line re qu ire ment for a 90-day or a l toxicity study !O PPTS 870 . 31 00; OECD 408 ) in the mou se . COMf>LIA_NCE: Signed and d ated GLP, Quality Assu r a nce , F l agging, and D a ta Confidentiality statements were provided . I. MATERIALS AND METHODS A.**~lA TE~Ut\.LS** **:** 1. Test m:<!_tcrial: Oe.scl'ipti o n : Lo t / B:1t t h #: Purit y: C:om JI O und Stahility:

CA S No . u fTGAI :

S tr uct ur e .

JR5l{78 Wh it<.: crystalline powder l Mch t--;o . FCFiTf\72-00 (ex 205 '25/ 03 i 8) 98 . 0'\ ' o a.i . Stahle in rodl!nt**di~:t** for 15 days at f'n.:c ling t emperature : :1nd fo r 3 days at room t emperature 213464 - 77-l'! 0 OCH 3**---** Jl ),**rrr~i( N~H~**  N<=J)**~ANI ·Jro** **NHCONH'JS: N~OCH** **3** 2. Vehicle and /o r positive control: T he test ma terial was inco rpor ated into the diet. N o positive cont ro l wa<; used in th i s study. 3. Test**anim~tls:** Species: S tra i n : Agtlweighl al s tud y initiation: S ource : Housing: Die t: \\ ' ater: Environm.-nta l c ondition s: Acclimation per i od: B. STUDY J>ESIGN:

Mnu5.: CD-t Appro xima te l y 40-44 ll ays of age I males : 31-32 g: fema l es: 25-26 g Charles Riw r ( U K ) Limited, Mllrgatc. Kent, England

Hous ed two of the s ame sex p a cage in polycarbom t te cages with.**stainle~~** steel mo::sh l i ds Rat and Mouse No . I Mai n te n ance Diet (Spec i al D i ets Serv i ces Ltd. , Witham.**Es~..:x.** E n gland) . ad /ibuum Tap \Vater. ud libitum Temperature: 1 9-23 ° C Humidity: 40-70% Air c ha nges : ,: 15 timcslhr Ph o t op e r i od: 12 hrs d ar k/ 12 hrs l ight 14 days 1. In life dates: Start: November I. 200 0 ; .En d: January 3 1- Feb rua ry I , 2001 2. Animal assignment: Animals were ra ndomly assigned to the t est groups noted in T able 1 . Two males. whose body weights were at t he ext reme ends of the weight ran ge of the other m i ce. wen:: r eplaced by two spare males fr om th e sa me ba tch of animals .IR5878/ PC Code 108209

Test group Cone
. in diet fDDm} Control 0 Low 250**~1id** 1250 Hi11h 6QOO 'Da1 a fro m page 39 ol MRID 46260102
. Subchroni c (90-day) Oral Toxic-ity Study (Mice} (20(11) Page 3 of II OPPTS 870.3100 I OECO 408 TABLE :1 : Study design Dose to animal #Mall! #Female (m1!/k2/davl" 0 10 10 <1'{3(> )**~** (47) 10 10 c· ( 187) 'i' (228) 10 10 d'

_

l&65)**~** {)0961 10 10 

### 3. Dose scl_!!ction rationale: The dose l evels were selected based on the results f rom a four-week oral toxicity study in mice (Report No
. AGR126/000096) where animals were administere d 0
. 50, 250. 1250, or 6000 ppm in the diet. Decreased body weight gains and incrcns ed liver weights were observed in males at 6000 ppm, but females were unatlected by treatmc m at all dose levels tested. 4. Diet preparation and analysis: Premix was prepared weekly by mixing appropriate amounts o f test substance with Rat and Mouse No. 1 Maintenance Diet. Test: diets were then prepared -..v ..::ek 

### ly by serially di l uting the concentrated premix
. Homogeneity and stability of IR5878 in the feed, at concentrations of 50 and 12500 ppm , were tested in an earlier study (Report No
. AGR 1 27 /003821); however, the results of this study were not provided in MR£0 46260 I 

### 02. During the 90-day study, sampl es of treated food from each te s t group were**an lyz<;** **d** 

### on weeks l, 6, and 12 

### tor active ingredient concentration using a solvent extraction me t hod, followed by reverse phase 

### HPLC analysis with external cal ibration. Res u lts:**Homo~ene ty**  

### a n alysis: Homogeneity was confirmed at nominal concentrations of 50 and 12500 ppm in an earl i er study (Report No. AGR 127/ 003821 ); however. the results of this study were not reported in MRID 46260 I02. Stability**~malysis:** 

### Stability ofIR5878 in the diet was confirmed for 15 days with freezer storage and for 8 days with storage at room temperature; however. results of the stability analysi s were not reported in MRID 46260102. Concentr-Ation analysi s: Dietary concentrations were 95-99% , 94-97%, and 93-100% of targe t c onct.=ntrations for the low-, mid-. and high-dose groups, respectively. The a nalytical d ata indicated that the variance between nominal and actual dosage to the animab w a s acceptable. 5. Statistics: Body weights and organ weights were tested for homogeneity of variance using Bartl e tt 's te s t. If signi ticant, a Behrens

- F isher test. was used for pairwise comparison s ; 

### if not sign i
. ficant. Dunnett ' s test was used. Gross pathological and histopathological findings were anal y ze d u sing Fisher's exact test to compar e each treated group with contro ls . 

# f\IR5878 I PC Cod t · IIJ8209 Su b c hroni c (90-day) Oral Tox ici t y Study (Mi ce} (2011 1 ) Page 4 of II OPPTS 870. 310 0 I OECO 408 F o r clinic a l pathology data, if75% of t he fi.n di ngs (across all treatment groups) were t h e same number , then a frequency analysis was conducted. T re atmen t groups were compared using a Mantel test and pairwise Fisher's Exact tests. I f Bart l ett's test was not s i gnificant at the 1% level, parame t ric analysis was conducted. Then , if the F I test was n ot sign if icant at the 1% level, W ill i an1s' test was applied, but if i t

was signif i c a n t at that level, Dunnett ' s t e st was u s e d.

If Bartlett' s re s t w a s sign i ficant at t he l% l eve l , the data were subjected to t ra nsfonnation to obtain equalit y ofvariancc and then t ested again using Bartlett's t est. If still signHicant , nonparametr i c analysis was appli e d. T h e n , if the H 1 t est was not significa n t a t t h e l% level,

Shirley' s t est w a s applied, bu t if i t was significa nt a t that level, S t ee l' s l est wa s u sed. 1 a . Cagcside observations: Animals we r e inspected twice a day for signs o f toxicity and mortal i t y. 1 b . ClinJg!l examination s: Clin i ca l obse rv atio ns wer e cond u cte d weekly . lc. Neurol o g i cal evaluations: Ne u ro l og i cal evaluations were not cond u cte d . 2. Body w e i g ht: Anima l s were weighe d p ri or to initiation of the stu d y, on the first day of dosing, wet.:kly during the dosing pe r i od, and before necropsy. 3. Food consumption and compound intak e: Food consumpt ion for each cage was determined , a n d m ea n w eekly diet consumpt i on was calculated as g food/anima l /w e ek. Food

efficiency was calc u la t ed o n a weekly ba s is as 100 x (g body weight gain per w e e k /g f oo d consumpti o n per week). Co m pound intak e (mg/kg bw/day) va lu es were calculated as time weighted a v erages fro m the consumption and body weight gain d ata. 4. OphthaJmoscopic examination: No ophthalmoscopic examinati . ons we re cond u cted ; h owever . t he eyes were observed durin g clinical, macropathological, an d histopathological examination s. 5. HematoJoey and clinical chemistry: Blood was co ll ected from the re tr o - orbita l 5 inus of all anima l s during week 13 for hematology and of all surv i ving animals at s t udy termination for clinical chemi s try. During sa mp ling , animals were held und er iso fl urane anesthesia . The C H ECK I : n (X) parameters were examin e d. 0**·** ( .I R5878 / PC C otl.- 1082119

llemawerit {H CT)• llc:mo gi nhin (HGB)• l .euk o l ·' t o: Cu tmt ( WH<.') • Erythl

**,,,~** h: ..:uunt I RR (')• Bl ood · :loumg measurements• **~ubc hroni** 

**c** (90-day) Oral T oxicity Stu d y ( Mi ce) (200 1 ) P ageS of II O PPTS 870.3 100 t 0EC0408

X Le ukoc yte d iftcrcntial count • Mean co rpuseu lar HG B ( MCI I)" Me a n cor pusc . HGB conc . (M C H(') • Mt:an corpusc. vt' lumc ( M CV)• Reticulocyte eo uut

• Recommended t\ •r <JII
. J ay oral rodent stu dies based on G.•iddinc 871)
. 3 I00

Not

**~amincd**



### b. Clinical chemistry:

1\lkal in-:

**pho~p atasc**  (ALP) •

**l'ho**

**ti csl\"-;1~e**  ( C hi-:) C rcatuw

**ph<>~p**
**ok masc**  l.ac tic i•citl deh yd roi!e nase ( LDI I 1 /\laniue nnunotrans l crasc (/\L' l l al so SGPT} • A s paru.tc .nnnwtransfcrase (AST / also SGO T)" Sorb itol

**dd1~drogcnase**

**•** tiamm;. g luwmyltransfemsc (liGT)"' Albumin * Creatinine• Urea nitrogen• l'otal Choleslero!• Glob u lin s Glucose • Total bili ru bin T otal pro tein (TP:· • Triglyccrides Seru m protein

**elc.::trophorc~is** Al bumin/ globulin ratio

• Recommended fi1 r 90-day oral rodent studic:s based on Guiddinc 87 0. 3100

- N ot examined 

### 6 . Urinalvsi s: Urina l ys i s was not conducted in t his study. 7
. Sacrifice and pathology : All animal s were sacrificed on schedu l e and were s ubjected to gross pathological exa mination ; the 

### CHECKED (X) tissues

**wen~** 

### co ll ected for hi stolo gical exami nation. The adrenal::>, cecum , colon, d uodenum, epi didymi des, esophagus. head, heart, ileum , jej unum. live r, lungs \\>1th mai nstem bronc hi , mandibular and mesenteric ly mph nodes, ovaries
. prostate. r ec tum , scia tic nerve , s to mac h, tes tes, thymu s , thyroid with parathyroids . trachea, urin ary b l adder , and the uterus with cerv ix were collected and preserved. but these organs wen: not examined histo log ical l y. The (XX) o rg ans , i n addition , were weig he d.IRS8 78 / PC C od (· 108209 S ubchronic (90 - day) Oral Tox icit y S t u d y (M ice) ( 2001) Page 6 of II OPPTS 870.3 1 00 I OECD 408 c:=ll lHGESIIYE**S~SIEM** lc::::JI**CABI!IQYA~. UEMAI.**  -**Ton~\ <:**  - Aorta***~** - Sa li var>**;~ an** **ds******* XX I lean*+ X**Esnplla :;:** **o~s*** - Bone marrow• X S t otn.1 c: h • X Lymph**node •**  X l ho•k n • n n • XX Sp lccn* ·t X**.l~ un** **-: 111** **"** XX T hymus'• IX Ile um" X Ccn : m b UROGENITAL X Colon• XX Ki dney s' •+ X K cct •. un' · X U r inary b ladder* XX L ive r · • .. XX Tes t es * +

- <ia ll i'>la d t kr ( not r at)* XX Epididymide s • ; - B ik t . Hcl (ra t) X Pro s t at <:' '**nt.: r~o** **a!'\ (**  - S e mina l vc ; m:lcs" H ES PIRA TORY X X Ovarks* + X Trad h .: < r' XX U t erus* + XX L Ull !-! ' ' - Mammary g l and•

X**Nos~ 1**  - Coagulating g land X**Phm:· '~'** **''** XX Cervix - . La r vnx• - Va2in'

" Re com mended l(ll 90-day oral rodent stud1es**ha~ cd**  on GUJdc hnc 870 . 3100 + O rg a n**wei ht~** **.** r e q ui r ed l o r ro dent**~ludic~.** - No t**wc ~h.:J**  w , .,ucc tcd fo r examinatio n 11. RESl/LTS A. OBSERYA T IONS :

l c=J I**EI BQl,QGIC**  XX Brain•+ r-x- 1· \:riphcra l n erve:• X Spinal cord (3 le v el s } * - Pituitary * - Ey e s (optic n e r ve )"' GLANDULAR X Ad r ena l gland* ·• - I , acrimal g l and X Paralhymid* X Thy ro id • OTHER

- B<>nc (sternum and/o r fem ur ) - S k<:lc t a l 11\ L t o d <: - Sk in * X Al l gross lesi ons and**ma~se •**  X H ead ( i nc l ud in g nasal ..: a v i ty, para nas al**sin u~** **s,** m t sopharynx) 1. Clinical signs of toxicity: No**treatment~related** cl in ical signs w ere observ e d. 2 . Mortality: One control ma le and on e m i d -dos e female were sac r if iced during week 13 for humane .reasons (both suffered eye damage durin g blood sampling) . Otherwise, no u ns cheduled mortalities occurred dur i ng th e st udy. B . BODY WEIGHT AND W E IGHT GAIN: Mean b ody we i g ht s and t otal bod y we ight gains are giv en in T abt e 2 . There were no treatment-related effects on body weights or body we i g h t g::t i ns i n this stu dy .

IIR587 8/ P C C udc 10 8 2 09 S u bc hro nic (9 0-d ay) Ora l T o xid ty S tudy (Mice I ( 20111 ) Page 7 of II OPPTS 8 7 0.3 100 I O E CD 4 0 8
TABLE 2. Mea n body weights and body w e ight gains during 90 d : 1vs of treat ment " O ost' 

### p Bo d y wei g h ts ( g :1: S D) Total Weig ht (ppm ) Week-I We ek I W e ek 7 Wee k 13 Gain (g ) Male 0 31.0± 2 11 ] 4.2:!: 2
. 5 4 1.5 J. 4
. 1 43 6 :!: 5
. 4 12
. 6 250 30
. 5 ± 1. 9 ]4
. 3 :1: 1. 9 4 1. 0 ± 3
. 4 4 3.9 ± 2.9 13
.4 1 2 50 3 0
. 8 ± 3 0 34.3:1:3
. 1 42.3 :1: 4.0 4 4
. 1 ± 6.9 13
. 3 6000 31.9:r 1.7 34
. 9 :! : I.X 41
. 7 :1: 2
. 8 4 2
. 8 ± .3
. 6 10
. 9



## - Femal e 0 25 .1 :t. 1.7 26
. 7:1: 1.7 29 ..1 ·:!- 2
. 3 30.0± 2
. 5 4
. 9



## - 250 25 .0 ± 0 .9 26
. 6 ±I 6 30 7 :i 2
. 1 30 .5:!: 

### :u; 5.5



## - 125 0 26.4 :!: 2.4 27
. 5 :1: 2
.2**30.~ :!:**  3 .3 J U \±4.0 5. 4 600 0 25
. 2 ± 1.3 26
. 7 ± 1.4 30
. 3 ± 2
.2 30
. 1 :!: 2
. 7 49 'Da ta (> blam ed ! rom pages J2-3J m the s-t u dy re port . 

### C. FOOD CONSUMPTION AND COMPO U ND I NTAKE : 

### 1. Food consumption: Foo d cons umption was co mp arab le between groups fo r m ales
. In t reate d kmales, f oo d con s umptio n was s lightly l o w er than in control f e m ale s (Tab le 3 )
. T A B L I': 3
. Mean fo o d con s um p ti o n of fe male mice at selected interval s during 90 d ays o f tre atm e n t' Do s e (ppm ) Week l W eek 7

0 38 ± 5 4 1 ±6 25 0 33 ± 3 39±4 1250 32± J 3 9 ± 4 _6000 34 ± 2 _3_&_ ±_6

' Daw obtained frt•ll1 pages 36

- 37 in the study rep o rt. • Results in pan:nt hc s c o: a re percen t ages 

### or contro ls
. F ood c o nsumption (glweek ± SO)**W~ek** 1 0 W ee k 13 Weeks l-J3b 45 J: 4 4 5 : t 3 550 ( 1 00 ) 4 0 i: 7 3 8 .1:5 503 (91 ) 39 ± 4 35 : t. 4 4 9 9 (91) 36± 4 3 7 :l: 5 4 &4 ( 88}.



### 2. Compound con s umption: Time -w eighted av erage compound intak e s are s how n in Tabl e I. 3. Food effici«m£Y: C o m pa red to control s , foo d e ffic iency w as marg ina lly dec re ased in hi gh

do se mak<;. 

### D
. OPHTHALMOSCOPIC EXAMINATlON: Ophthalmo sc opic e x a minatio ns we re no t co n ducte d in 

### L h is st u dy
. 

### E
. 

### BLOOD**AL**

### YSES: l. 

### Hematology: S elect e d h e mato l ogy parameters are pre se nted i n Tab le 4. I n mal es , a marginal dec rease in ly mpho c)1 CS was seen in t he hig h -do s e group c omp are d to con trols; howeve r . thr s 

### effec t was nol 

### seen i n treated tcmales or in t he low

- or mid- do se ma l0 groups . 

# ,,Jl.-3 

# a·IR S878/ PC Codt• 108209 Subc hr o nic (90- d ay) O ral T oxic i ty S tud y ( M ice) (200 1 ) Pa ge 8 or II 0 PPTS 870.3100 I OECD 408 In **fe e::~**  **,** tht: m ean corpuscula r hemo g l obin (MCH) and m ean corpusc ul a r volu me ( M CV) v a lues v.e rc s lig ht l y decreased i n all tr eated g r oups compared to c ontrols; no .. change i n MCH or MCV was found in male s. TABLE 4. Select ed hema t ology finding s in mi ce followi n g 90 da ys o f t rea t ment with IR 5878 '" i M a le Dose Ly m phocyte MCII (ppm) cou nt (pg± S D ) (I 0 ' 9 / L :.t S O) 0 7 5 ± 1.8 16.4 J: o . 7 25 0 6 . 1 · • · I 7 1 5 . 6±0 . 5 125 0 5 s ± 2 . 3 1 5 . 9 ± 0 . 5 6000 4 .7 ·t 2 . 7 .. 15 . 9 :1: 0 . & • D at a o t> ta m ..:cl lr. • nt **p< g(:~**  4 0 -4 2 an t ho.: st ud y rep o r t. .. p < \).0 1

female MCV L ,y mp hocyte M C H MCV (fL :i: S D ) cou nt (pg ±S O) (fL ± SD) (lQ- 9 / L ± S D ) 5 1 :l t 1. 5 3. 1 ± 1. 6 L 7 . 0 :t: 0 . 5 54 .6 :!; 1 . 8 49.-1 r 1.5 2 . 5 :1: l.l 16 J :1: 0.4 •• 52 . 2 . I I.J • •

50 I ::1: 2 .3 3 . 0 ± 1 . 0 16 . 4 J.() . 7 •• 51.8 ± 2 . 2 .. 5U . 9 r2 . U 3 . 5 ± 1.2 16.4 ±0.4 ·· 52.2 ± 1. 5 • • 2. Clinical chemi stry: There were n o treatment-related effects on clinic al chem i s tr y i n this study. F. URINALYSIS: U rin a l ys i s was no t conducted in t h i s st u dy. G . SACRIFICE AND PATHOLOGY: I. On:an weieht: Abso lu te and re l ative l iver weig h ts wer e marg ina ll y inc r ease d in high -d ose males compared to contro l s, but only th e change in li ve r weights r e l ative to body weig h ts was s tati stically s ign i ficant. Female l ive r weights were unaffec t ed by treatment. Absol ut e heart we i gh t s were s l igh tly dec r eased, compar ed t o co ntr ols, in h igh-dose females on l y. Statis t ically sign ificant decr eases in mid-d ose male thymu s w eights a n d l ow -d ose female u t e r us/cen · ix. weights were not attr ibut ed to tr ea t ment s inc e s imil ar inc reases were not see n at hi g her dnsl! le vels. TA BLE 5 . Absol u te a n d rela t ive live r w ei e . hts ( mean ± S O ) i n mice follo w in e 90 davs of treatment w ith JR58 7 8' Dose Male Female ( p pm) Body weigh t Livcr Liver / body Body weight Liver Liver/ b ody " (g ) (I!.) (2 Iiv e r .I IOO 1!.) {2) <el (2 li ver / 100 e) 0 1 2 . 2 :: J 8 I. <J ± 0.4 4. 5 l 0.6 29 . 6 t. 2.4 1. 5 :1: 0 . 3 5 .2 +. 0 . 6 25()

**~** () I 3. 1 1.9 ± 0 . 3 4.5 ± 0 .5 29.9 ± 2.4 1.5 :1: 0.2 -< . 9 ± 0 .4 1 250 13 · I **~** 6 .4 2. 1 ±(U 4 . 8 :1: 0 . 5 30 . 1< ± 4.2 1 5 :1: 0.2 :. o ± 0. 5 - 6000 e:! .. 2 . 9 2.2 f: 0 .3 5 . I -1: ().5 • ( I 1 4 )b 29.4 + 2.7 1.6 ± 0 . 2 :\ . 4 +. 0. 6 3 D a t a ob tam c d hu m **pag~:~** 4!1- 53 10 the stu d y r epo rt . " R es u lts i n **n: n!h,**  **~c'** a r c p .:rc c n l o f .:o ntml cal cu lat ed by th o: r..:' i..: " ..: r. " Sig. mf i c a ntl y d i l k o .:nl f'rt'lll c.:< •nlrt )b. p · (} 05IR5878/ PC Code 108Z09 Suhchronic (90-day) Oral Toxidty Study (Mit: e) (2001) Page 9 of 11 OPPTS 870.3100 I OECD 408 2. Gross pathology: There were no treatment-related changes observed. Although several animals ( o n e low-dose, two mid -do se, and two high-dose males, plus one control and three low-dose Jcmales) had abnorma l findings in the lymph nodes, th ese effects appeared sporadic an d not relate d to dose. 3. Microscopic patholo&V: There were no treatment-related changes observed. Of the animals with abnormal gross pathological fin d ings in the l ymph nodes, th ree (one mid-dose male, one**high -d** **o~ c**  male. and one low-dose female) had reactive histiocytosis: however, these effects were sporadi<..: and not considered to have been related to dos in g . 

### III. DJSCl iSSION AND CONCLUSIONS A. 

### INVESTIGATORS ' CONCLUSIONS: T he study authors conduded th at, in male CO- l mice. die tary exposure to f R 5878 near the l imit dose caused slight changes in body weight gai ns, 

### lood convers ion efficiency, and liver weights. The increase in male \iver weights was considered minima l
. • adaptive. and not toxicologically significant. In females, the limit dose of 

### £R5878 was associated with lower f(,od co n sumption, but the investigators did not consider this effect toxicologically significant since no change in body weights or body weight gains 

### v.as seen . Therefore, the study a uth ors determined that th e 

### NOAEL was 6000 ppm , which is equival ent to 865 mg/kg/day for male mice and to 1096 mg/kg/day for female nuce . 

### B. REVIEWER COMMENTS: The reviewer concurs w ith the study au tho rs' concl u sion that dietary exp0sure to 

### 1R5878 for 90 days caused minimal, non-toxicologically significant changes in male and female CD-I mice. These changes include slightly decreased food consumpti o n by high-dose females, with no changes in body weights or body weight gains compared to controls. Also, compared to controls, mean MCH and MCV values were marginally dec re ased in all treated female groups, and mean lymphocyte counts were slightly decreased in hig h-dos e males; however, these decreases were not biologically significant. Absolute and relative male liver weights were slightly increased compared to controls. but only the change in relative liver weights of the high-dose animals reached statistical s ignificance
. Furthermore, no treatment-related changes were see n in clinical chemistry, gross pathology
. or histop ath o lo gy to suggest liver or other toxi ci ty. The 

### LOAEL was not identified in tbis study 

### (>865 mglkg/day for males and 

### >1096 mglkg/d ay for females). The 

### NOAEL is the highest dose tested in this study 

### (6000 ppm), whi ch 

### was equivalent to 

### 865 mglkg/day for males and 

### 1096 mglkglday for females. Oosing in this study is considered adequate because the highest dose tested is sufficiently close to the limit dose of 

### 1000 mg/kglday. Th is stud y is Acceptable/Guideline and satisfies th e gui d eline requirement**t~)r** 

### a 90-day oral toxicity study (O PPT S 870.3100: OECD 408) in the mouse.

( /'
. '\ 

## d ,.IR58 78/ P C Code 10820 9 Su bchron i c (90-day) Oral T o xic i t y S tud y (Mice) (2001) Pa ge 1 0 o f II OPPTS 870.3 1 00 I OECD 408 C. ST U D'\' l>EFICIENCIES: E xamina ti ons of the following pa ramete r s/o r gans, which ar e**reconun~nded** by the gu i d eline s for a 90-day oral t oxicity study i n r odents, w ere not**pc for** **~d:** b l ood clotting potential, cr ea ti nine, urinalysis, a n d ga ll b ladde r . Add i tio nally , ad r enal**.~ and**  weigh t s, whi c h are r equired by the g u i de l ine s, w er e not repo rtt::d . Alt hough not

a ll or t he guid eline recommendations and requi re ments were a d dressed i n this s tudy, t h is docs no1 i nval id ate t h e study results . )\ 1