IR5878/ t•C Codf 108209 

Subchronic (90-day) Oral Toxicity Study (Rats) (2<l0l) Page I of 15 

OPPTS 870.31 00 I OECD 408 

EPA P rima ry 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) 

TXR#: 0052629 

Signature: 141 /4--..c.L-. Date {/;IV c..;-

Signature: at;,;. (~ , ~tJ 

Date wlu../? . / g tto./-

Tcmplar.;;' ,,ersion 1110 I 

DATA EVALlJATION RECORU 

STUDY TYPE: 90-Day Oral Toxicity Feeding Study- Rats; 

OPPTS 870.3100 (§82-la); OECD 408. 

PC COI>E: 108209 DP BARCODE: 0306738 

SUBMISSION NO.: 8755326 

TEST MATERIAL (PURITY): lR5878 (Orthosulfamuron, 98.0%) 

SYNONYMS: 1-( 4.6-dimethoxypyrimidin-2-yl)-3-[2-( dirnethylcarbamoyl)-pheny lsulfamoyl] 

urea; benzamide, 2-[[[[[(4,6-dimethoxy-2-

pyrimidinyl)arninoJcarbonyl jamino jsulfonyl]amino }-.K -N -dimethylCITATION: Webley, L. (200 1). IR5878 Toxicity study by dietary administration to Han 

Wistar rats for J 3 weeks followed by a 4 week recovery period. Huntingdon 

Life Sciences Ltd, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, 

England PE28 4HS. Study No. AGR 128/012174, October 16.2001. MRID 

46260 I 03. Unpublished. 

SPONSOR: lSAGRO SpA, Centro Uffici San Siro - Fabbricato D. ala 3. Via Caldera, 2 1, 

20153 Milano- Italy. 

EXECUTIVE SUMMARY: In a 90-day subchronic oral toxicity study (MRID 46260103). 

IR5878 (98.0(YI• a. i .. Batch No. FCFIT/ I 72-00 (ex 20525/03/8) was administered to ten Han 

Wistar rats/sexidose in the diet at dose levels ofO, 250. 1500. and 9000 ppm (equivalent to 0, 19, 

113. and 706 mg/kg bw/day, respectively, for males and to 0, 22, 131 , and 773 mglkg bw/day, 

respectively. for females). Concurrently, a recovery group of five Han Wistar rats/sex/dose were 

administered either 0 or 9000 ppm (equivalent to 0 or 706 mg/kg bw/day, respectively, for males 

and to 0 or 773 mg!kg bw/day, respectively, for females) during the 90-day study period and were 

then maintained for an additional four weeks on the control diet. 

There were no compound-related effects on mortality, body weights, body weight gains, food 

consumption, nl.!uro logical observations and measurements, hemat<>logy, clinical chemistry, or 

gross pathology. Compared to controls, an increase in dorsal hair Joss was seen in females, but 

this finding i:-; C•)mmon. Other treatment-related effects (transient increases in liver weight and 
IR5878/ PC Cndc 108209 

Subchronic (90-day) Oral Toxicity Study (Rats) (2001) Page 2 of 15 

OPPTS 870.3 100 I OECD 408 

hepatocellular hypertrophy in high-dose males compared to controls) indicate a minimal, 

adaptive response in the liver following exposure to IR5878 that is 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 oral 

toxicity study (()PPTS 870.3100; OECD 408) in the rat. 

COMPLIANCE: Signed and dated GLP. Quality Assurance, Flagging, and Data Confidentiality 

statements were provided. 

I. MATEfUALS AND METHODS 

A. MATERIALS: 

l. Test material: 

Descripl ion: 

Lot/Batd• #: 

Purity: 

Compound Stability: 

CAS No. ofT<;AI: 

Structure: 

IR5878 

White crystalline powtkr 

Batch No. FCFff/ 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 days at ronm temperature 

213464·77-8 

2. Vehicle and/or oositive control: The test material was incorporated into the diet. No 

positive control was used in this study. 

3. Test animals: 

Specie.~: 

Strain: 

Age/weight at study 

initiation: 

Sourn: 

Bousing: 

()iet: 

Water: 

Environmental conditions: 

t\cclimation period: 

Rm 

l-Inn W1star 

Approximately 37-41 d:~y$ of age I males: 135-138 g. females: 108-112 g 

ll<trlan UK Lim1ted. Bic.:cstcr. Oxfordshire, England 

Housed live of the same sex per cage in stninlcss steel cagt:s with stainless stcd mesh 

I ids and floors 

Rilt <Jnd Mouse No. I Maimcnance Diet (Special Oiets Services Ltd .. Witham. Essex, 

f. ngland). ad libilllm 

., ap water, "d libitum 

Temperature: 19-23"C 

Humidity: .((). 70% 

Air changes: , 15 timcs/hr 

Photoperiod: 12 hr~ darkil2 hrs light 

I I days 

2 

\.\ 
1R5878/ PC Cudt> 108209 

B. STUDY DESI GN: 

Subthr onic (90-day) Oral Toxicity Study (Rats) (200 1) Page 3 of IS 

OPPTS 870.3 100 I OECD 408 

1. In life dates: Start: November 20, 2000 

End: February 19-20.2001 (Main group); March 19,2001 (Recovery group) 

2. Animal assignment: Animals were randomly assigned to the test groups noted in Table I . 

Three mall!s with body weighl<; at the extreme ends of the weight range of the other rats and 

two males with ophthalmic lesions were replaced by five spare males from the same batch of 

animals. ,\tlhe end of the regular study. the recovery groups were held for an additional four 

weeks, du ring which they w<.·re fed the l:Ontrol diet. 

I T ABLE 1: Study design I 

Test group 

Cone. in d iet Dose to animal II Male II Female loom) ov\' 

Control 0 0 10 10 

Low 250 f {19) ~ (22) 10 10 

Mid 1500 c:'( l13 )~( 13 ) 10 10 

Hi!!h 9000 c! (706) ~ l773l 10 10 

Recoverv Gr.ouD 

Control 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 levels were selected based on the results from a 

four-week oral toxicity study in rats (Report No. AGR125/000095) where dietary 

administration of up to 12500 ppm resulted in changes in body weight gains. food 

consumption. hematology, clinical chemistry, and spleen weights. These changes were also 

seen at 2500 ppm. Because the high dose, 12500 ppm, was considered sufficiently 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 mixing appropriate 

amounts or test substance with Rat and Mouse No. 1 Maintenance Diet. Test diets were then 

prepared weekly, three days in advance, by diluting the concentrated premix and were stored 

frozen. Homogeneity and stability of lR5878 in the feed, at concentrations of 50 and 12500 

ppm, were tested in an earlier study (Report No. AGR 127/003821 ); however, the results of 

this study v.ere not provided in MRTD 46260103. During the 90-day study, samples of 

treated f(wd from each test group were analyzed on weeks 1, 6, and 12 for active ingredient 

concentration using a solvent extraction method, followed by reverse phase HPLC analysis 

with extemal calibration. 

Results: 

Homogeneity analysis: Homogeneity was confirmed at nominal concentrations of 50 

and 12500 ppm in an earlier study (Report No. AGR 127/00382 1); however. the results of 

this stuJy were not reported in MRID 46260103. 

3 

./, 

... • 
IR5878 / J>C Codl' 108209 

SubciJronic (90-day) Oral Toxicity Study (Rats) (2001) Page 4 of IS 

OPPTS 870.3100 I OECD 408 

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 an earlier study (Report No. 

AGR 127/003821); however, results of the stability analysis were not reported in MRID 

46260 I 03. 

Concentration analysis: Dietary concentrations were 97-99%, 94#98%, and 92-96% of 

target concentrations for the low-, mid-, and high-dose groups, respectively. 

The analytical data indi cated that the variance between nominal and actual dosage to the 

animals was acceptable. 

5. Statistics: Body weights and organ weights were tested for homogeneity of variance using 

Bartlett's test. lfsignif1cant, a Behrens-Fisher test was used for pairwise comparisons; if not 

significant. Dunnett's test was used. Gross pathological and histopathological findings were 

analyLed u::oing Fisher's exact test to compare each treated group with controls. 

For clinical pathology data, if75% of the findings (across all treatment groups) were the 

same munbcr, then a frequency analysis was conducted. Treatment groups were compared 

using a Mantel test and pain-vise Fisher's Exact tests. 

If Bartlelt's test was not significant at the 1% level, parametric analysis was conducted. 

Then. if the .. : F I test was not significant 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 transformation to 

obtain equality of variance and then tested again using Bartlett's test If still significant, nonparametric analysis was applied. Then, if the HI test was not significant at the 1% level, 

Shirley'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 twice a day for signs of toxicity and 

mortalily. 

lb. Clinical examinations: Clinical observations were conducted weekly. 

lc. Neurological evaluation~: The following observations were made on ten 

animals/group/sex prior to initiation of the study and weekly during the dosing. period 

and on all of the recovery phase animals in the final week ofthe recovery period: 

exophthalamos, fur condition, lacrimation, piloerection, reactivity to handling, ease of 

removal from cage, salivation, vocalization, activity counts, arousal, convulsion, 

defecation counts, gaiL grooming. palpebral closure, posture, rearing, tremor, twitching, 

and urination. The following measurements were recorded prior to ~tudy initiation and 

I; 

I.J' 
IR5878 / PC C01le 108209 

Subchronic (90-dRy) Oral Toxicity Study (Rats) (2001) PageS of 15 

OPPTS 870.3100 I OECD 408 

dunng week 12 of the dosing period for 10 animals/group/sex and during week 4 of the 

rcco'.ery period for all of the recovt:ry phase animals: approach response. auditory startle 

relkx. body temperature, body weight. grip strength, landing footsplay, tail pinch 

response. pupil reflex, righting refl ex, touch response, and motor activity. 

2. Body wdellt: Animals were weighed prior to initiation of the study, on the tirst day of 

dosing. weekly during the dosing and rel:overy periods, and before necropsy. 

3. Food consumption and compound intake: Food consumption for each cage was 

determined. and mean weekly diet consumption was calculated as g food/animal/week. 

Group rnenn food efficiencies were calculated on a weekly basis as I OO*(g body weight gain 

per weck/g tood consumption per week). Compound intake (mglkg bw/day) values were 

calculated as time-weighted averages from the consumption and body weight gain data. 

4. Qnhtha lmoscopic examination : Eyes of all animals were examined before dosing (week 

-1 ) using indirect ophthalmoscopy. Eyes of all surviving control and high-dose animals were 

also simil arly examined during week 13. In both cases, a 0.5% tropicamide solution was 

instilled prior to examination. 

5. Hematolon a nd clinical chemistry: After an overnight fast, blood was coJlected from the 

retro-orbital sinus of all main study animals during week \ 3 and from all recovery study 

animals m week 4 of the recovery period. Duri ng sampling, animals were held under 

isotluranr..: anesthesia. The CHECKED (X) parameters were examined. 

X 

a. Hematolot::Y: 

Hcmntocrit (IICT)• 

Hemogl<•hin tiiGB)* 

LcukCX:;> ll' count (WBC)• 

ryth ;yt~ count tRRC)* 

la lt:t ~:r•u nt • 

Alond d oli ing. measurements* 

{Thrc•mbopla.~tin time) 

Leukocyte differential count• 

Mean corpuscular HGB (MCH)* 

:vtean corpusc. 11GB cun.c. (MCHC)* 

Mean corpusc. volume (.\IICV)• 

Reticulocyte count 

• Recommended''-" 'JO-day oral rodent studies ba. d on Guideli ne 870.3100 

- Nl)\ ~xamino.:d 

5 
Subchronic (90-day) Oral Toxicity Study (Rats} (200 l} Page() of I 5 

IR5878 / 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 Cholcsl<!roJ• 

<llobulins 

Sodiu:n• Glucose* 

ll---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-cs-)*'--·tl---il Total bilirubin 

i\ lkalitlo.:: phosrhatase (ALK)'• Total protein (TPl* 

Cholin:'l<'rasc (ChEl Trig.lycerides 

OTHER 

('n:aii no.: plwsrhokinasc Serum protein electrophoresis 

La~ti' ;,cid dehydrogenase (LOl l) Albumin/globulin nllio 

/\lanitiL' :uuinNmnsfcrasc (/\LT/also SGPT)• 

Aspart<~ c <iiHinotransterase (ASTialso SG(}I)t 

Sm\>ilul lkh (\rogenasc~ 

Cianuua glurarnyllransferasc (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 from 

fasted n.:.:(.overy phase animals during week 4 of the recovery period. The CHECKED (X) 

parameters were examined. 

Specifi( 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 were sacrificed by carbon dioxide inhalation and were 

subjected to gross pathological examination; the CHECKED (X) tissues were collected for 

histological examination. The head, larynx, nose, pharynx, salivary gland (one only), sciatic 

nerve (one only), and skeletal thigh muscle (one only) were collected and preserved, but thes.e 

organs \Wn.: not examined histologically. The (XX) organs, in addition, were weighed. 

6 
IRS878 / PC Ctldc 108209 

n rc:F.STIVIi. SYSTF.M 

- Ton!fUO.: X 

X SalivJr~ g.lands• XX 

X Esoplwgus~ - X Stom.;ch"' X 

X DunJ.:nam• XX 

X llll!Ul" '~ XX 

X llcU!r' 

rx- (\:ctun• 

X Colon• XX 

X Rectum" X 

XX Li\O.:I"l . XX 

- Gall \•la•hkr• (not rnl) XX 

- - 13ilc cttll X 

X f>ancr.:a.-" X 

l{l:SPIRATORY XX 

X TradJ<~ · XX 

X Lun!!' X 

X N<>s<·' 

X Pharvn.\ ' 

X L 'IT\'11' • 

Subchronic (90·day) Oral Toxicity Study (Rats) (2001) Page 7 of IS 

OPPTS 870.3100 I OECO 408 

( "4RnlOV4S( ./HF.MAT. J'lEI IROI.OC.:If 

Aort<\* XX Brai11~ + 

lleart•+ X Peripheral nc:rw:• 

Bont: marrow* X Spinal cord ( 3 k:\•c:b)• 

Lymph node,• X Pituitary• 

Spleen• • X E}es (optic nerve)" 

l1lymus•+ CLANOtJLAR 

XX Adrenal gland*+ 

URO<;ENITAL X Lacrimal gland 

dney~ + XX r•arathyroiu'" 

Urinary bloddt\r• XX Thyroid• - Testes•·~ 

Epididymidc + 

Prostatc* OTHER 

Seminal v.:sidcs• X Bone (sternum and lemur) 

Ovnri..:~ + X Skeletal musch: 

Uterus• ... X Sl..in• 

Mammary gl1111d • X All gross lc:stons anol n1asses• 

X 1-lead 

• Recommend..:1: f1'r 90-duy oral rodent studaes ha.scd on (Jtuddtne S70.3 100 

·l Organ weight, rl'<: uircd lor rodent studil-s 

- Not examin.:d 

7 
Subchronic (90-day) Oral Toxicity Study (Rats} (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. RESULTS 

A. OBSE~V A TIONS: 

1. Clinical si~ns of toxicity: The only treatment-related clinical sign of toxicity observed was 

hair loss from the dorsal body surface, beginning on week 1 for both males and females. Hair 

loss wa.s fllund in 3/10, 2110, and 6/15 of the low-, mid-, and high-dose males. respectively. 

compared to 0/ 15 of control males. In ft~males, 4/10, 4/ 10, and 12/15 animals were affected 

in the low-. mid-, and high-dose groups, respectively, compared to 2/15 of control females. 

Although no hair loss was seen in control and high-dose males during the recovery period. 

215 of the ~:onlro l females and 5/5 of the high-dose females also exhibited hair loss during the 

four week recovery phase. 

2. Mortality: No treatment-related mortalities occurred during the study. One control female 

had overgrown and maloccluded teeth and was sacrificed during week four for humane 

reasons. 

3. Neurological evaluations: Mean forelimb grip strength values were lower in all treated 

males compared to controls during treatment week 12. However, no dose-response was 

observed, and none of the differences between treated and control males were statistically 

significant. Forelimb grip strength in females and hindlimb grip strength in both males and 

females were similar to controls at all treatment levels. 

As shown in Table 2, a statistically significant increase in mean landing footspJay was seen in 

high-dos~~ females compared to control ft::males in week 4 of the recovery phase. Prior to 

treatmem, no difference in mean landing footsplay between ten control and ten high-dose 

females was observed. However, an examination of the individual data indic;ated that the 

landing f\)otsplay values for just those females that were examined on recovery week 4, in 

addition to treatment weeks 0 and 12, differed before the initiation ofthe study. Specifically, 

on treatment week 0, footsplay 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 phase of the 

study. No differences in landing footsplay were seen between any of the treated females on 

treatmem \Veek 12 compared to the control femalt:s or between any of the treated males 

compared to control males on treatment week 12 and recovery week 4. 

As shown in Table 3, statistically significant decreases were seen in the number of high-beam 

breaks made on treatment week 12 by low- and mid-dose males compared to controls. 

However. prior to the initiation of the study, the number of high-beam breaks made by the 

these low-· and mid-dose males were also lower compared to controls, although the 

differences were not statistically significant. No dose-response was seen; the number of 

high-beam breaks made by high-dose males did not differ trom controls. Compared to 

controls, thl' number of high-beam breaks made by females and the number oflow-beam 

breaks math.· by both males and females were unaffected by all levels of treatment. 
IRS878/ PC Code 108209 

Subchronic (90-day) Oral Toxicity Study (Rats) (200 l) Pllge 9 of 15 

OPPTS 870.3100 I OECD 408 

TABLE 2. Mean lllnding footsplav_(mm ::1: SO) in rats fed IR5878 for lJ weeks'' 

Males Females 

Dose 

(ppm) Treatment Treatment Recovery Treatment Treatment Recovery 

Week ()b Week llh Week 4' WeekOb Week 12b Week4' 

0 ~(1 ::1: 13 128 ± II 120 :!: 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 NiA 84 ::1: 19 117 ± 10 N/A 

9000 .81 :1: 17 133J:I3 125 :.1: I I 81 :1:9 101!± 17 101 ::1: 15 . 

·'Data oblamcd !rom pages 336-338 m the ~tudy report. 

• n = I 0. intluding tho~c 5 animals observed al recovery wc.:k 4 

• n = 5 

• Signili~.;an l~ .llff.: nl (rom controls, p•, 0.05 

Ti\BLJ:: 3. 1\tean moto,. activity (beam breaks ± SD) over 60 minutes in rats fed IR5878 for 13 weeks• 

Males 

Oosc(ppm) 

Treatment Treatment Recovery 

WeekOb Week 12~ Week 4' 

High beam breaks 

0 <JO± 26 147 ± 41 161 :t 105 

250 58± 35 95 ±J8 .. N!,'\ 

1500 73 r 59 107 ± 30. N/,\ 

9000 JO I ±51 125 ± 44 103 ± 36 

Low beam br eaks 

0 410± 124 697 ± 180 640 ± 204 

250 291 ::1: 159 H6 t. 182 NIA 

1500 368 ± 125 594 ±12 1 N/ A 

9000 -+54 ;; 254 624:!: 248 664 ± 83 

'Data obtarncd lnm1 pages 342-346 m tht: udy n:pon. 1

' n = I 0. induding rho::c 5 animals observed at recovery week 4 

' n = 5 

* Signilkantly dil fcrcnt from controls. p··0.05 

H Signilicantly ;~, f.:.n.mt fi·om control~. p; O.OI 

Females 

Treatment Treatment Recovery 

Week Ob Week 12b Week 4' 

99 :t 45 13 1 :I: 42 Ill .±: 44 

83:!: 56 107 ± 38 NIA 

79 :!: 30 99 ± 41 Nit\ 

1!3 .:!: 3Y 114 :1: 37 X7 ± 70 

358:!:: 144 623 ± \30 482 :!: 198 

358 :t 100 555 ± 136 NIA 

41 7 ~ 148 584 ± 161 N/A 

376 ± 139 663 ± 173 563 ± 328 

I 

B. BODY WEIGHT AND WEIGHT GAIN: Mean body weights and total body weight gains 

are given in Table 4. There were no treatment-related effects on body weights or body 

weight gains in the main or recovery phases of this study. 

9 
IR5878 / PC Cod(~ 108209 

Subchronic (90-day) Oral Toxicity Study (RatsJ (2001) Page 10 of 15 

OPPTS 870.31 00 I OECD 408 

TABU: 4. Mean body wel2.hts and bodv wei2.ht 2.ains (SWG) durin!!. 90 days of treatment" 

Dose Body weights (g ::1: SD) BWG (g) - Body weights (g ± SD) BWG (g)- (ppm) r--· Treatment Recovery 

Wel•kO Week I Week 7 Week 13 Period Rerovcry Recovery Period WeekO Week4 

Male 

0 I 1~ .I X 175 ± II 318 ± 26 367 .t 32 230 365 ± 26 384 l: 23 19 

250 J.l(• ± 6 176 ± 9 318 * 29 369 I· )8 233 Nl i\ N IA Nfi\ 

1500 u .< ! : t 172 :d i 306 .1: 2 1 356 !· 28 221 Nil\ N/1\ Nil\ 

9000 13(> I: 6 173 -;!: 8 3 11 t 28 367 ± 40 231 398 ± 53 422 ±52 24 

Female 

0 101; t. X 127 ± 12 188 ± 22 2 11 .1: 22 103 196 :l I I 204 = J() 7 

250 I ll I. 6 132 l 10 197 ± 27 221 :1.. 25 I 10 N/A Ni A NIA 

1500 I I:: '5 132 :1: 7 194 ± 13 214 :l:o 16 102 l'-I A N/A NfA 

9000 Ill :f 6 133 ± 8 196± 16 22 1 !: 16 109 230 ± 17 239 ± 17 9 

• Data ohtaincd f··~ nJ pages 43-45 in th<: stud)' rc:port. 

C. FEED ONSUMPTION AND COMPOUND INTAKE: 

l. Feed consumption: There were no treatment-related effects on food consumption. 

2. Compou_nd Intake: Time-weighted average compound intakes are shown in Table 1. 

3. Feed Efficiency: There were no treatment-related effects on food efficiency. 

D. OPHTl(ALMOSCOPIC EXAMINATION: There were no trei\tment-related 

ophthalmological findings. 

E. BLOOD ANALYSES: 

1. Hematology: Selected hematology data are given in Table 5. Mean red blood cell (RBC) 

counts were marginally decreased in high-dose females jn the main study compared to 

controls, but this decrease (-6%) is not biologically meaningful. Additionally, no significant 

decreases in mean RBC counts were seen in the low- or mid-dose main study females, the 

high-dose ~males following a four week recovery period, or in any of the treated male 

groups. 'Vhite blood cell and lymphocyte counts were slightly decreased in all treated male 

and female groups following 13 weeks of treatment with IR5878; however, these parameters 

were comparable to controls for both males and females following a four week recovery 

period. 

10 
IRS878 / 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 hematology findings in rats fed IR5878 for 13 weeks• 

Dose 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· Recovery 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\!rcnt 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-related changes reported. 

G. SACRIF]CE. AND PATHOLOGY: 

l. Organ weight: Compared to controls. liver and kidney weights relative to body weights 

were marginally increased in high-dose males following l3 weeks of treatment, ac; shown in 

Table 6. liowcver, male absolute liver and kidney weights in the main study and male 

absolute and relative liver and kidney weights following four weeks of recovery were all 

comparabk to controls. 

Absolute kidney weights in high~dose females were marginally increased compared to 

controls alkr the tour week recovery period. However, female absolute and relative liver and 

II 
IRS878/ PC Ct1de 108209 

Subchronic (90-day) Oral Toxicit~ Study (Rat~)(2001} Page l2 of lS 

OPPTS 870.3100 I OECO 408 

kidney wctghts in the main study, femak relative kidney and liver weights following 

recovery . and female absolute liver weight!:i following recovery were a ll comparable to 

controls. 

TABLE 6. Absolute and relatin organ weights in rats fed 1R5878 for 13 weeks' 

O OSt' Body weight Liver Liver/body Kidney 

(IHlm} (g) (2) (g/100) (g) 

Male Main Group - Treatment Week 13 

0 369 ± 35 122 ± 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 356 ± 29 I 1.6 .J: I :1 3.2 1: 0.2 1.9±Ct.2 

9000 35 I ± 20 13.5 ± 1.1 :>.9 = 0.2 •• 2.0 ± 0.1 

Male Recovery Gr oup- Recovery Wetk 4 

II 384 1: 29 13.5 ±1.7 3.5 ± 0.2 2.1 ±0.1 

90~0 422 t 53 13.9 ±1.1 3.3 i. 0.2 2.2 ± 0.2 

Female Main Gn>up- Treatment Week 13 

r---

n 21 5 :1: 2h 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 

151)(1 2 16 ± 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<emale R~co very G roup - R(COvery 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 sludy rcpc•rt. 

• Signii'i.:alllly different from c0ntrols, ~O.OS 

•• Significantly 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 mcrease in the adrenal gland absolute weights following 13 weeks of dosing 

occurred ml y in low-dose (not in mid- or hi gh-dose) females compared to controls. 

2. Gross patho)oi!)': There were no treatment-related gross pathology findings. 

3. Microscopic patholo~: On treatment week 13, slight centrilobular hepatocyte hypertrophy 

was seen in 7/ 1 0 of the high-dose males (Table 7), which correlates with the increase seen in 

relative ltver weights. Hypertrophy was also seen in lllO of the mid-dose males on treatment 

week 13, but none was seen in low-dose or control males. No hepatocellular hypertrophy 

was observed in females after 13 weeks or treatment or in males or females after a 4 week 

recovery period. 

12 
IR5878/ PC Cod~ 108209 

Subchronic (90-day) Or al Toxicity Study {Rats} (2001) Page 13 of 15 

OPPTS 870.3 I 00 I OE.CD 408 

TABLE 7. Incidence of centrilobular hepatocvle hv ertrophy in rats fed JR5878 for JJ week.~' 

Dose :Vlale Main Group- Male Recovery Group- Female Main G1·oup - Female Recovery Group 

(ppm) Treatment Week IJ Recovery Week 4 Treatment Wet k 13 - Recovery Week 4 

0 0/ 10 Oi5 0/10 Oi5 

250 0110 Ni l\ Oi!O Ni l\ 

1500 1! 10 N!/\ 0/1() N//\ 

9000 7110 .. 0/5 0/ 1(1 0/5 

.\ Data obtmnl!d II vn1 pages 85 and R9 111 the study report. 

*• Signifil·antl~ diikl\'rll lr(lll\ controls, pd).OI 

III. DISC(ISSION AND CONCLUSIONS 

A. INVESTIGATORS' CONCLUSIONS: The study authors concluded that, in Han Wistar 

rats, diet0.ry exposure to IRS878 caused dorsal hair loss in females, slight decreases in female 

red blood cell counts, hematocrit, and hemoglobin values: decreases in male and female 

white blood cell and lymphocyte counts and in phosphorous levels; changes in male 

creatinin.:: l:oncentration, triglyceride levels, a->partate amino-transferase and alkalinephosphatas(: activities, and urine composition; increased male liver and kidney weights; and 

an increase in the incidence of slight centrilobular hypertrophy of male hepatocytes. The 

investigators found no evidence of neurotoxicity. 

The inv~stigators report that the effects seen in male liver (i.e., increased liver weight and 

hepatoceLlular hypertrophy) were not seen following the four week recovery. The study 

authors determined that the NOAEL was 1500 ppm, which is equivalent to 11 3 mg/kg/day 

for male rals and to t3l mg/kg/day for female rats. 

B. REVIEWER COMMENTS: Dietary exposure to 1R5878 in rats did not cause any 

treatment-related effects on mortality, body weights, body weight gains, food consumption, 

neurological observations and measurements, hematology, clinical chemistry. or gross 

patholog). The statistically significant increases in the relative kidney weights of males and 

of absoluh: kidney weights in females (following recovery) are not biologically significant. 

Dorsal hair lt>ss in female rat<; is considered a treatment-related effect ofiR5878 exposure; 

however. hair loss is a common clinical sign with unclear toxicological significance. 

The treatment-related increase in relative liver weights seen in males administered 9000 ppm 

is considereJ to be an adaptive response, because liver weights were comparable to controls 

following a tom week recovery period. there were no biologically significant changes in liver 

enzymes. th~rc were no gross pathological effects in the liver, and there were no 

histopathological effects in the liver other than slight transient centrilobular hepatocyte 

hypertroph) 

13 
I RS878 I PC Ct>dt· 108209 

Subchronic (90-day) Oral Toxicity Study (Rats) (2001} Page 14 of IS 

OPPTS 870.3100 I OECD 408 

The LOAl L was not identified in this study (>706 mglkg/day for males and >773 

mg/kglday for females). The NOAEL is tbe highest dose tested in this 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 oral 

toxicity study (OPPTS 870.3 1 00; OECD 408) in the rat. 

C. STUDY DEFICIENCIES: Homogeneity of the test compound was confirmed at nominal 

concentrations of 50 and 12500 ppm in an earlier study (Report No. AGR I 27/00382 1 ). 

While sampks of the actual prepared diet used in MRID 46260103 were not tested for 

homogem:ity. this does not invalidate the study results. 

l4 
lR5878 / 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 

~ S1gna • t ure: aJA '.l. -<; I (. J , .~ £ , :21 

Date '1'1'faa . 1 4e>.£~5 

Tcmplat~ version I I !0 I 

OAT A EVALUATION RECORD 

STUDY TYP(~: 90-Day Oral Toxicity Feeding 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 

urea: benzamide, 2-r[[[[(4,6-dimethoxy-2-

pyrimidinyl )amino ]carbonyllaminojsul fonyllamino]-N -N-dimethylCITATION: Webley, L (2001). TR5878: Preliminarytoxicitystudybydietary 

administration to CD-I mice for 13 weeks. Huntingdon 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- Italy. 

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 20525/03/8) was administered to ten 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. gross pathology, or histopathology. Compared to controls, slight decreases in food 

consumption. MCH. and MCY in high-dose females and slight decreases in the lymphocyte 

count of high-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 sufficiently 

close to the limit dose of I 000 mg/kg/day. 

(l 
.. 

IR5878/ P(' Code 10820? 

Subcbronic (90-day) Oral Toxicity Study (Mice) (2001) Page 2 of II 

OPPTS 870.3 WO I OECO 408 

This study is Acceptable/Guideline and satisfies the guideline requirement for a 90-day oral 

toxicity study !OPPTS 870.31 00; OECD 408) in the mouse. 

COMf>LIA_NCE: Signed and dated GLP, Quality Assurance, Flagging, and Da ta Confidentiality 

statements were provided. 

I. MATERIALS AND METHODS 

A. ~lA TE~Ut\.LS : 

1. Test m:<!_tcrial: 

Oe.scl'iption: 

Lot/B:1tt h #: 

Purity: 

C:omJIOund Stahility: 

CAS No. ufTGAI: 

Structure. 

JR5l{78 

Whit<.: crystalline powder 

lMch t--;o. FCFiTf\72-00 (ex 205'25/03i8) 

98.0'\'o a.i. 

Stahle in rodl!nt di~:t for 15 days at f'n.:cling temperature ::1nd for 3 days at room temperature 

213464-77-l'! 

0 OCH3 

--- Jl ), rrr~i( N~H~ N<=J) 

~ANI·Jro NHCONH'JS: N~OCH3 

2. Vehicle and/or positive control: The test material was incorporated into the diet. No 

positive control wa<; used in this study. 

3. Test anim~tls: 

Species: 

Strain: 

Agtlweighl al study initiation: 

Source: 

Housing: 

Diet: 

\\'ater: 

Environm.-nta l conditions: 

Acclimation period: 

B. STUDY J>ESIGN: 

Mnu5.: 

CD-t 

Approximately 40-44 llays of age I males: 31-32 g: females: 25-26 g 

Charles Riwr (UK) Limited, Mllrgatc. Kent, England 

Housed two of the same sex pa cage in polycarbomtte cages with. stainle~~ steel mo::sh 

lids 

Rat and Mouse No. I Maintenance Diet (Special Diets Services Ltd., Witham. Es~..:x. 

England). ad /ibuum 

Tap \Vater. ud libitum 

Temperature: 19-23°C 

Humidity: 40-70% 

Air changes: ,: 15 timcslhr 

Photoperiod: 12 hrs dark/12 hrs light 

14 days 

1. In life dates: Start: November I. 2000; .End: January 31-February I, 2001 

2. Animal assignment: Animals were randomly assigned to the test groups noted in Table 1. 

Two males. whose body weights were at the extreme ends of the weight range of the other 

mice. wen:: replaced by two spare males from the same batch of animals. 
IR5878/ PC Code 108209 

Test group 

Cone. in diet 

fDDm} 

Control 0 

Low 250 

~1id 1250 

Hi11h 6QOO 

'Da1a from page 39 ol MRID 46260102. 

Subchronic (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 levels were selected based on the results from a 

four-week oral toxicity study in mice (Report No. AGR126/000096) where animals were 

administered 0. 50, 250. 1250, or 6000 ppm in the diet. Decreased body weight gains and 

incrcnsed liver weights were observed in males at 6000 ppm, but females were unatlected by 

treatmcm at all dose levels tested. 

4. Diet preparation and analysis: Premix was prepared weekly by mixing appropriate 

amounts of test substance with Rat and Mouse No. 1 Maintenance Diet. Test: diets were then 

prepared -..v..::ek ly by serially diluting 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 127/003821); however, the results of this study were not provided in 

MR£0 46260 I 02. During the 90-day study, samples of treated food from each test group 

were an lyz<; d on weeks l, 6, and 12 tor active ingredient concentration using a solvent 

extraction method, followed by reverse phase HPLC analysis with external calibration. 

Results: 

Homo~ene ty analysis: Homogeneity was confirmed at nominal concentrations of 50 

and 12500 ppm in an earlier study (Report No. AGR 127/003821 ); however. the results of 

this study were not reported in MRID 46260 I 02. 

Stability ~malysis: Stability of IR5878 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 

analysis were not reported in MRID 46260102. 

Concentr-Ation analysis: Dietary concentrations were 95-99%, 94-97%, and 93-100% of 

target conct.=ntrations for the low-, mid-. and high-dose groups, respectively. 

The analytical data indicated that the variance between nominal and actual dosage to the 

animab was acceptable. 

5. Statistics: Body weights and organ weights were tested for homogeneity of variance using 

Bartlett's test. If signi ticant, a Behrens-Fisher test. was used for pairwise comparisons; if not 

signi.ficant. Dunnett's test was used. Gross pathological and histopathological findings were 

analyzed using Fisher's exact test to compare each treated group with controls. 

f\ 
IR5878 I PC Codt· IIJ8209 

Subchronic (90-day) Oral Toxicity Study (Mice} (2011 1) Page 4 of II 

OPPTS 870.3100 I OECO 408 

For clinical pathology data, if75% of the fi.ndings (across all treatment groups) were the 

same number, then a frequency analysis was conducted. Treatment groups were compared 

using a Mantel test and pairwise Fisher's Exact tests. 

If Bartlett's test was not significant at the 1% level, parametric analysis was conducted. 

Then, if the F I test was not significant at the 1% level, Willian1s' test was applied, but if it 

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

If Bartlett's rest was significant at the l% level, the data were subjected to transfonnation to 

obtain equality ofvariancc and then tested again using Bartlett's test. If still signHicant, nonparametric analysis was applied. Then, if the H 1 test was not significant at the l% level, 

Shirley's test was applied, but if it was significant at that level, Steel's lest was used. 

1 a. Cagcside observations: Animals were inspected twice a day for signs of toxicity and 

mortality. 

1 b. ClinJg!l examinations: Clinical observations were conducted weekly. 

lc. Neurological evaluations: Neurological evaluations were not conducted. 

2. Body weight: Animals were weighed prior to initiation of the study, on the first day of 

dosing, wet.:kly during the dosing period, and before necropsy. 

3. Food consumption and compound intake: Food consumption for each cage was 

determined, and mean weekly diet consumption was calculated as g food/animal/week. Food 

efficiency was calculated on a weekly basis as 100 x (g body weight gain per week/g food 

consumption per week). Compound intake (mg/kg bw/day) values were calculated as timeweighted averages from the consumption and body weight gain data. 

4. OphthaJmoscopic examination: No ophthalmoscopic examinati.ons were conducted; 

however. the eyes were observed during clinical, macropathological, and histopathological 

examinations. 

5. HematoJoey and clinical chemistry: Blood was collected from the retro-orbital 5inus of all 

animals during week 13 for hematology and of all surviving animals at study termination for 

clinical chemistry. During sampling, animals were held under isoflurane anesthesia. The 

CHECK I :n (X) parameters were examined. 

0 

(. · 
IR5878 / PC Cotl.- 1082119 

llemawerit { HCT)• 

llc:moginhin (HGB)• 

l.eukol·' t o: Cutmt ( WH<.')• 

Erythl ,,,~ h: ..:uunt I RR(')• 

Blood ·:loumg measurements• 

~ubchroni c (90-day) Oral Toxicity Study (Mice) (200 1) PageS of II 

OPPTS 870.3 100 t 0EC0408 

X Leukocyte diftcrcntial count• 

Mean corpuseular HGB (MCI I)" 

Mean corpusc. HGB conc.(MCH(')• 

Mt:an corpusc. vt'lumc (MCV)• 

Reticulocyte eouut 

• Recommended t\•r <JII.Jay oral rodent studies based on G.•iddinc 871). 3 I 00 

Not ~amincd 

b. Clinical chemistry: 

1\lkal in-: pho~p atasc (ALP)• 

l'hoti csl\"-;1~e (Chi-:) 

Crcatuw ph<>~p okmasc 

l.actic i•citl dehydroi!enase ( LDI I 1 

/\laniue nnunotranslcrasc (/\L'l lalso SGPT}• 

Asparu.tc .nnnwtransfcrase (AST/also SGOT)" 

Sorbitol dd1~drogcnase• 

tiamm;. gluwmyltransfemsc (liGT)"' 

Albumin* 

Creatinine• 

Urea nitrogen• 

l'otal Choleslero!• 

Globulins 

Glucose• 

Total bilirubin 

Total protein (TP:·• 

Triglyccrides 

Serum protein elc.::trophorc~is 

Albumin/globulin ratio 

• Recommended fi1r 90-day oral rodent studic:s based on Guiddinc 870.3100 

- Not examined 

6. Urinalvsis: Urinalysis was not conducted in this study. 

7. Sacrifice and pathology: All animals were sacrificed on schedule and were subjected to 

gross pathological examination; the CHECKED (X) tissues wen~ collected for histological 

examination. The adrenal::>, cecum, colon, duodenum, epididymides, esophagus. head, heart, 

ileum, jejunum. liver, lungs \\>1th mainstem bronchi, mandibular and mesenteric lymph nodes, 

ovaries. prostate. rectum, sciatic nerve, stomach, testes, thymus, thyroid with parathyroids. 

trachea, urinary bladder, and the uterus with cervix were collected and preserved. but these 

organs wen: not examined histologically. The (XX) organs, in addition, were weighed. 
IRS878 / PC Cod(· 108209 

Subchronic (90-day) Oral Toxicity Study (Mice) (2001) Page 6 of II 

OPPTS 870.3100 I OECD 408 

c:=ll lHGESIIYE S~SIEM lc::::JI CABI!IQYA~. UEMAI. 

- Ton~\ <: ~ - Aorta* 

- Salivar> ;~ ands * XX I lean*+ 

X Esnplla:;: o~s* - Bone marrow• 

X Stotn.1c:h • X Lymph node • 

X lho•kn•nn • XX Splccn*·t 

X .l~ un -: 111 " XX Thymus'• IX Ileum" 

X Ccn:mb UROGENITAL 

X Colon• XX Kidneys'•+ 

X Kcct•.un'· X Urinary bladder* 

XX Liver·• .. XX Testes*+ 

- <iall i'>ladtkr (not rat)* XX Epididymides• ; 

- Bik t.Hcl (ra t) X Pros tat<:'' 

nt.: r~o a!'\ ( - Seminal vc;m:lcs" 

HESPIRA TORY XX Ovarks*+ 

X Tradh.:<r' XX Uterus*+ 

XX L Ull!-! ' ' - Mammary gland• 

X Nos~ 1 - Coagulating gland 

X Phm:·'~' '' XX Cervix 

- . Larvnx• - Va2in' 

" Recommended l(ll 90-day oral rodent stud1es ha~cd on GUJdchnc 870.3100 

+ Organ wei ht~. required lor rodent ~ludic~. 

- Not wc ~h.:J w , .,ucctcd for examination 

11. RESl/LTS 

A. OBSERYA T IONS: 

lc=JI EI BQl,QGIC 

XX Brain•+ 

r-x- 1·\:riphcral nerve:• 

X Spinal cord (3 levels}* 

- Pituitary* 

- Eyes (optic nerve )"' 

GLANDULAR 

X Adrenal gland*·• 

- I ,acrimal gland 

X Paralhymid* 

X Thyroid• 

OTHER 

- B<>nc (sternum and/or femur) 

- Sk<:lcta l 11\Ltod <: 

- Skin* 

X All gross lesions and ma~se • 

X Head (inc luding nasal ..:avity, 

paranasal sin u~ s, mtsopharynx) 

1. Clinical signs of toxicity: No treatment~related clinical signs were observed. 

2. Mortality: One control male and one mid-dose female were sacrificed during week 13 for 

humane .reasons (both suffered eye damage during blood sampling). Otherwise, no 

unscheduled mortalities occurred during the study. 

B. BODY WEIGHT AND WEIGHT GAIN: Mean body weights and total body weight gains 

are given in Tabte 2. There were no treatment-related effects on body weights or body 

weight g::tins in this study. 

I 
IR5878/ PC Cudc 108209 

Subchronic (90-day) Oral Toxidty Study (Mice I (20111 ) Page 7 of II 

OPPTS 870.3 100 I OECD 408 

TABLE 2. Mean body weights and body w eight gains during 90 d:1vs of treatment" 

Oost' p Body weights (g :1: SD) Total Weight 

(ppm) 

Week-I Week I Week 7 Week 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 41.0 ± 3.4 43.9 ± 2.9 13.4 

1250 30.8 ± 3 0 34.3:1:3. 1 42.3 :1: 4.0 44. 1 ± 6.9 13.3 

6000 31.9:r 1.7 34.9 :!: I. X 41 .7 :1: 2.8 42.8 ± .3.6 10.9 

- Female 

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 - 1250 26.4 :!: 2.4 27.5 :1: 2.2 30.~ :!: 3.3 J U \±4.0 5.4 

6000 25.2 ± 1.3 26.7 ± 1.4 30.3 ± 2.2 30.1 :!: 2.7 49 

'Data (>blamed !rom pages J2-3J m the s-tudy report. 

C. FOOD CONSUMPTION AND COMPOUND INTAKE: 

1. Food consumption: Food consumption was comparable between groups for males. In 

treated kmales, food consumption was slightly lower than in control females (Table 3). 

T A BLI': 3. Mean food consumption of female mice at selected intervals during 90 d ays of treatment' 

Dose 

(ppm) Week l Week 7 

0 38 ± 5 41 ±6 

250 33 ± 3 39±4 

1250 32± J 39 ± 4 

_6000 34 ± 2 _3_&_ ±_6 

' Daw obtained frt•ll1 pages 36-37 in the study report. 

• Results in pan:nthcsco: a re percentages or controls. 

Food consumption (glweek ± SO) 

W~ek 10 Week 13 Weeks l-J3b 

45 J: 4 45 :t 3 550 ( 100) 

40 i: 7 38 .1:5 503 (91 ) 

39 ± 4 35 :t. 4 499 (91) 

36± 4 37 :l: 5 4&4 (88}. 

2. Compound consumption: Time-weighted average compound intakes are shown in Table I. 

3. Food effici«m£Y: Compared to controls, food efficiency was marginally decreased in highdose mak<;. 

D. OPHTHALMOSCOPIC EXAMINATlON: Ophthalmoscopic examinations we re not 

conducted in Lhis study. 

E. BLOOD AL YSES: 

l. Hematology: Selected hematology parameters are presented in Table 4. In males, a 

marginal decrease in lymphoc)1CS was seen in the high-dose group compared to controls; 

however. thrs effect was nol seen in treated tcmales or in the low- or mid-dose mal0 groups. ,,Jl.-3 a· 
IRS878/ PC Codt• 108209 

Subchronic (90-day) O ral Toxicity Study (M ice) (200 1) Page 8 or II 

0 PPTS 870.3100 I OECD 408 

In fe e::~ , tht: mean corpuscular hemoglobin (MCH) and mean corpuscula r volume (MCV) 

values v.erc slightly decreased in all treated groups compared to controls; no .. change in MCH 

or MCV was found in males. 

TABLE 4. Selected hematology findings in mice followi ng 90 days of treatment with IR5878'" 

i Ma le 

Dose Lymphocyte MCII 

(ppm) count (pg± SD ) 

(I 0'

9

/L :.t SO) 

0 7 5 ± 1.8 16.4 J: o. 7 

250 6. 1 ·•· I 7 15.6±0.5 

1250 5 s ± 2.3 15.9 ± 0.5 

6000 4.7 ·t 2.7 .. 15.9 :1: 0.& 

• Data ot>tam..:cl lr. •nt p< g(:~ 40-42 an tho.: study repo rt. 

.. p< \).01 

female 

MCV L,ymphocyte MCH MCV 

(fL :i: S D) count (pg ±SO) (fL ± SD) 

(lQ-9/L ± SD) 

51 :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 16J :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 chemistry: There were no treatment-related effects on clinical chemistry in this 

study. 

F. URINALYSIS: Urinalysis was not conducted in this study. 

G. SACRIFICE AND PATHOLOGY: 

I. On:an weieht: Absolute and relative liver weights were marginally increased in high-dose 

males compared to controls, but only the change in liver weights relative to body weights was 

statistically significant. Female liver weights were unaffected by treatment. Absolute heart 

weights were slightly decreased, compared to controls, in high-dose females only. 

Statistically significant decreases in mid-dose male thymus weights and low-dose female 

uterus/cen·ix. weights were not attributed to treatment since similar increases were not seen at 

higher dnsl! levels. 

TABLE 5. Absolute a nd rela tive liver weie.hts (mean ± SO) in mice follo wine 90 davs of treatment with JR5878' 

Dose Male Female 

(ppm) 

Body weight Livcr Liver/body Body weight Liver Liver/body 

"(g) (I!.) (2 Iiver.IIOO 1!.) {2) <el (2 liver/ 100 e) 

0 12.2 :: 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 

1250 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 14 )b 29.4 + 2.7 1.6 ± 0.2 :\.4 +. 0.6 

3 Data obtamcd hum pag~:~ 4!1-53 10 the study report. 

"Results in n:n!h,~c' arc p.:rcc nl of .:ontml calculated by tho: r..:' i..:" ..:r. 

" Sig.mficantly d ilk o.:nl f'rt'lll c.:<•nlrt)b. p· (} 05 
IR5878/ 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 (one low-dose, two mid-dose, and two high-dose males, plus one control and three 

low-dose Jcmales) had abnormal findings in the lymph nodes, these effects appeared sporadic 

and not related to dose. 

3. Microscopic patholo&V: There were no treatment-related changes observed. Of the animals 

with abnormal gross pathological findings in the lymph nodes, three (one mid-dose male, one 

high-do~ c male. and one low-dose female) had reactive histiocytosis: however, these effects 

were sporadi<..: and not considered to have been related to dosing. 

III. DJSCliSSION AND CONCLUSIONS 

A. INVESTIGATORS' CONCLUSIONS: The study authors conduded that, in male CO-l 

mice. dietary exposure to fR5878 near the limit dose caused slight changes in body weight 

gains, lood conversion efficiency, and liver weights. The increase in male \iver weights was 

considered minimal .• adaptive. and not toxicologically significant. In females, the limit dose 

of £R5878 was associated with lower f(,od consumption, 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 authors determined that the NOAEL was 6000 

ppm, which is equivalent to 865 mg/kg/day for male mice and to 1096 mg/kg/day for female 

nuce. 

B. REVIEWER COMMENTS: The reviewer concurs with the study authors' conclusion 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 

consumption 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 decreased in all treated female groups, and mean lymphocyte counts were slightly 

decreased in high-dose 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 

significance. Furthermore, no treatment-related changes were seen in clinical chemistry, 

gross pathology. or histopathology to suggest liver or other toxicity. 

The LOAEL was not identified in tbis study (>865 mglkg/day for males and >1096 

mglkg/day for females). The NOAEL is the highest dose tested in this study (6000 

ppm), which 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. 

This study is Acceptable/Guideline and satisfies the guideline requirement t~)r a 90-day oral 

toxicity study (OPPTS 870.3100: OECD 408) in the mouse. 

( /'. '\ d ,. 
IR5878/ PC Code 108209 

Subchronic (90-day) Oral Toxicity Study (Mice) (2001) Page 10 of II 

OPPTS 870.3100 I OECD 408 

C. STUD'\' l>EFICIENCIES: Examinations of the following parameters/organs, which are 

reconun~nded by the guidelines for a 90-day oral toxicity study in rodents, were not 

pc for ~d: blood clotting potential, creatinine, urinalysis, and gall bladder. Additionally, 

adrenal .~ and weights, which are required by the guidelines, were not reportt::d. Although not 

all or the guideline recommendations and requirements were addressed in this study, this 

docs no1 invalidate the study results. 

)\1