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AR226-2919 FOR DU PONT USE ONLY E . I . du Pont de Nemours and Company In c . H a ske ll Lab oratory for Toxicology and In d u s tria l Medicine E lk to n Road, P . 0 . Box 50 Newark, Delaware 19714 HASKELL LABORATORY REPORT NO. HLO-387-84 Haskell No. 15,388 Other Codes Study Initiated/Coiwpleted 6/11/84 - 6/18/84 c M a te ri a l S u b m itte d 1 polymer Products Department Washington Works EYE IRRITATION TEST IN RABBITS Haskell Evalu ation : a skell Standard Operating Procedure fo r eye ir r ita tio n t e s t i n g was followed] s are given ^ n the appendix. In th e unwashed e y e , produced moderate c o n ju rc tiv a l r e d n e s s ,'s lig h t conjunctiva, chemosis, ^ w i t f i c le a rin g by seven d ays . In the washed e y e ,! t f H | f l p r o d u c e d m ild conjun c tiv a l redness w ith " E e s W o b y t h i s p r o c e d u r e , is a moderate eye irrita n t. C o m p o sitio n : *5yn on ym s: j I - 1Company Sanitized. Does not contain T S C CB? Report by: Reviewed b y: Carol S . Auletta/Donna L . Blaszcak Bio/dynamics In c. George W. L o v e t t , M .D . c u anH Pve S tu d ie s C o o rd in a to r Acute Investigations Approved by: Associate Director GWL/egg Date Issued: August 30, 1984 Haskell Lab. Report No. HL0-3B7-B4 .... Appendix attached: 10 pp, Bio/dynamics Pro je c t No. 5227-84 T o ta l pages in t h i s r e p o r t : 12 i a Blo/clynamics Inc. Division of Biology and Safety Evaluation PROJECT N O .: 5227-84 EYE IRRITATION STUDY IN RABBITS TEST MATERIAL: HL 15,388 S u b m itte d t o : E . I . du Po n t de Nemours & Company H a s k e ll L a b o r a t o r y f o r T o x ic o lo g y and Industrial Medicine E l k t o n Road, P . 0 . Box 5C Newark, Delaware 19711 ! ICfcmpany Sanitized. Does not conta* T e r A m t Ilio/'a y n arrile in e - 1 5227-84 I . INTRODUCTION T h is s tu d y was conducted f o r E . I . du P o n t de Nemours & Company t o e v a lu a te th e o c u la r i r r i t a t i o n produced by HL 1 5 ,3 8 8 i n r a b b i t s . The s tu d y was performed a t B i o / d y n a m ic s , I n c . , M e t t l e r s R o a d , E a s t M i l l s t o n e , New J e r s e y 08873 . Th is r e p o r t has been reviewed by the Q u a lit y Assurance U n it o f Bio/dynam ics, In c . to assure i t s conformance w ith the p ro to c o l and raw d a ta . A l l raw d a t a , th e o r i g in a l study p r o to c c 1 and f i n a l r e p o r t w i l l be r e ta in e d on f i l e in the Bio/dynamics Archives. I I . EXPERIMENTAL DESIGN No. Of Rabbits Amount o f M a te ria l - Eye s Washed/ Unwashed 1 10 mg Unwashed 1 10 mg Washed I I I . DATES OF STUDY: Animal R e c e ip t: In itia tio n (Dosing): Term in atio n (Last Observation): I V . STUDY PERSONNEL: Study D ire c to r: Laboratory Supervisor: Technician in Charge: Study M onitor (Report Preparation): V. STUDY CONDUCT V I. MATERIALS A. Test Animals: Breed: Reason for Selection: A p ril 30, 1984 June 1 1 , 1984 June 18, 1984 Carol S. A u le tta , B .A ., O .A .B .T . Donna L . B laszc a k, B . S ., AALAS R .L .A .T . Mary Webb, B . S . , AALAS Deborah M e ttin g , B .A . T h is study was conducted fo llo w in g Good Laboratory Practices. Albino Rabbits New Z e a la n d W hite Standard laboratory animal fo r ocular i r r i t a t i o n s t u d i e s . The New Z e a la n d W h ite breed was used because o f i t s a v a i l a b i l i t y and because o f the e x is t in g h is to r ic a l data base fo r comparative e valu atio n . Com pany SahTtizeH. Does noi contain T S C A CBt O I V I. MATERIALS (c o n t.) Supplier: Number: Age: Eq uilibration Period: Observations: Husbandry: Housing: Cages: Environmental Conditions: Food: Water: 'dv n a m )TM In i' - - 2 5227-84 Hazleton-Outchland, Inc. Denver, Pennsylvania Two (2 males) toung a d u lts 42 days A l l animals were checked fo r v i a b i l i t y twice d aily during the e q u ilib ra tio n period. P rio r to assignment to study a ll animals were examined to a sce rtain s u ita b ility for study. C urrently acceptable practices o f good animal husbandry were fo llo w e d , e . g . , Guide fo r the Care and Use o f Lab oratory A n i m a l s ; DHEW P u b l i c a t i o n N o . I N I H ) >8-23 EpvTseff 1978. In d iv id u a lly housed Suspended, stainless steel T e m p e r a t u r e : 6 0 - 7 0 #F i s c o n s id e r e d an acceptable temperature range for ra b b its ; room temperature was m onitored and recorded twice d a ily and maintained w ith in t h i s range to the maximum e x t e n t p o s s i b l e . H u m id ity: 30-702 is considered an acceptable humidity range fo r ra b b its ; room h u m id ity was m o n ito re d and re c o rd e d d a ily and m aintained w ith in th is range to t h e maximum e x t e n t p o s s i b l e . L ig h t cycle: 12 hours l i g h t , 12 hours dark (c o n tr o lle d by an autom atic tim er) La b R a b b it Chow HF (P u r in a #5326), ad libitum Autom atic w atering system, ad lib itu m M unicipal water supply (Eliza b e th to w n Water C o .) I ! V . MATERIALS (c o n t.) Id e n tific a tio n : Selection: Each animal was i d e n t i f i e d w ith a monel ear tag bearing a unique number p r io r to testing. Anim als were randumly placed in cages upon r e c e ip t and were placed on study as a v a ila b le a t the time o f study i n i t i a t i o n . Animals considered unsuitable fo r study because o f poor health or ocular abnorm alities were excluded from s e le c tio n . B. Test M aterial: D e s c rip tio n : Date of Receipt: Received from: Storage: V I I . METHODS HL 15,388 White powder May 2 1 , 1984 E . l . du P o n t de Nemours & Company Room te m p e ra tu re A. Duration of Study: A s i n g l e dose was a d m in is te r e d fo llo w e d by a 3 t o 7 day o b s e r v a t io n period. B. Route of Adm inistration: Ocular C. Ju s tific a tio n for Route o f Adm inistration: The stu dy is intended to provide in fo rm a tio n on the h e a lth hazards lik e ly to arise from a short-term accidental exposure to the te s t m aterial by the ocular route. D. Preparation of Anim als: - On the day f o r e d o sin g , both eyes o f each animal we-e examined using flu o r e s c e in dye t o check fo r presence o f corneal u lc e r a tio n . J u s t p r io r to t e s t substance a p p lic a tio n , the eyes were examined a g a in , but w ith o u t flu o r e s c e in . Anim als showing p r e -e x is tin g corneal or c o n ju n c tiv a l in ju r y o r i r r i t a t i o n were n o t placed on study. E . Preparation of Test M a te ria l: The t e s t m a t e r i a l was a d m i n i s t e r e d as r e c e i v e d ; no m i x t u r e was jp required. a jEbimpany Sanitized. Does not contain T S f'fl r m `Udyn a m i c s Ini'. -4 5227-84 V I I . METHODS (c o n t.) F . Adm inistration of Test Substance: 1. Dose: 10 mg 2. Adm inistration: The a p p ro p ria te amount o f the t e s t m a te ria l was in tro du c e d in t o the lower c o n ju n ctival sac o f the r i g h t eye o f each anim al. The upper and lower lid s were g e n tly held togeth er fo r one second p rio r to releasing to prevent loss o f m a te ria l. The c o n tra la te ra l eye served as the c o n tro l. 3. Wash: The tre a te d and co n tro l eye o f one animal remained unwashed. Tw e n ty seconds a f t e r th e t e s t substance was a d m in i s t e r e d , b o th e ye s o f th e re m a in in g animal was r i n s e d f o r one m inute w ith lukewarm water. V I I I . EXPERIMENTAL EVALUATION A. V ia b ility Check: Twice D a ily B. Evaluation of Ocular Ir r ita tio n : 1. Intervals: A p pro xim a te ly 1 and 4 hours and 1 , 2 , 3 and 7 days a f t e r tre a tm e n t, or u n til no signs o f I r r i t a t i o n were present. 2. Methods: A t each In te r v a l the tre a te d and co n tro l eyes were examined and scored fo r ocular reactions according to the D ralze scale (see Ap pendix A ) . F lu o re s c e in dye was .used to c o n firm presence or absence o f corneal u lce ra tio n in treated eyes s ta rtin g w ith the 24 hour o b se rva tio n and a t each subsequent o b s e rva tio n . Unusual e ffe c ts such as pannus, b lis te rin g o f the co n ju n c tiva , u lc e ra tion and o th e r e ffe c t s in d ic a tiv e o f c o rro s ive a c tio n were a ls o noted when p re s e n t. C om pany Sanitized. Does not contain T S C A CB1 __ B1% 'd.vnamics Ini'. -5 5227-84 I X . RLSULTS AND DISCUSSION Individual ocular observations are presented in Table I ; the scoring system used i s p resented in A p pend ix A . A summary o f 1) resp on se s c o n s id e re d p o s i t i v according t o 16 CFR 15 0 0 .4 2 [CONSUMER PRODUCT SAFETY COMMISSION, Fe d e ral Hazardous Substances Act R e g u la tio n s , T e s t fo r Eye I r r i t a n t s ] and 2) Maximum D r a iz e Scores i s presented in T a b le I I . HL 15.388 produced mild but re ve rsib le ocular ir r it a t io n in both the . washed and unwashed e y e s . Both eyes had m ild to moderate c o n ju n c tiv a l i r r i t a t i o n (re d n e ss , chemosis) and s l i g h t corneal and/or i r i d i a l changes. Both o f the anim als were fre e o f ocula r i r r i t a t i o n w ith in 3 to 7 days a ft e r in s tilla tio n o f the te s t m aterial. Responses in the non-rinsed eye were s im ila r to those in the rinsed eye. Th e re fo re , rin s in g o f the eye a fte r in s tilla tio n o f the te s t m aterial did not appear to have had a b e n e fic ia l e f f e c t . Carol S. A u le tta , B .A ., D .A .B .t . Study Director Manager, Acute Toxicology Date Com pany Sanitized. Does no! tr c a C8i -6 5227-84 KEY TO FOOTNOTES aScores given are fo r treated eyes. Unless otherwise noted, control (untreat ed) eyes had n egative scores fo r a l l param eters. Scored according to D ra ize Scale presented in Appendix A. *Twenty seconds a ft e r dosing, both eyes were rinsed w ith lukewarm water for one minute. f-O b se rvatio n confirmed w ith flu orescein . M-Male F-Fe m a le 'CompanySanitized. Does not contain TSCA CB1 TABLE I EYE IRRITATION STUOY IN RABBITS TEST M ATERIAL: HL 15,388 INDIVIDUAL OCULAR SCORESa Anim al N o . 3e~3 M Conjunctivae A . Redness B. Chemosis C. Discharge 0. Necrosis!N)/ Ulceration(U) Score Time A fte r Adm inistration Hours 1 IT lays 1 c3 7 11 12 00 00 46 21 1 0 1 100 0000 0000 6420 Iris Score 00 00 0000 0p00 Cornea A . Opaci ty B . Area C. Stippling D. Ulceration Score Other Total Score ++ 22 22 00 00 -- 46 000 0 000 0 000 0 Of Of Of Of 000 0 --- - 6420 Animal No. 3899 M* Conjunctivae A . Redness B . Chemosis C . Discharge D. Necrosis!N)/ Ulceration(U) Score 1 1 0 0 4 Iris Score + 0 1 1 0 0 4 0 0 1 10 000 000 0 00 220 000 00 0 Cornea A . Opacity B . Area C. Stippling D. Ulceration Score Other Total Score 00 00 10 00 00 -- 44 00 0 000 0 00 Of Of Of 000 --- 220 Key to fo otnotes presented on page 6. -7 5 2 2 7-8 4 Positive Score 24, 48, 72 Hr. (p e r 16 CFR 15 0 0 .42 ) Yes No No No No No No No No No No No SCoiflpany S an itize d. Does hot contain T S C A CB1 TABLE II EYE IRRITATION STUDY IN RABBITS TEST MATERIAL: HL 15,388 SUMMARY O F RESPONSES AND MAXIMUM D R A IZ E SCORES P o s i t i v e ( + ) o r N e g a t i v e ( - ) S c o r e s 8_______ Maximum D raize Score Time C1earb Cornea Iris C o n j u n c t i v a e ................. ........ Animal Necrosis or Number O p ac ity U lc e ra tio n Redness Chemosis U lc e ra tio n Score F i r s t Time Obtained Un washed 3893 M - - - - 6 4 Hour Day 7 Mashed 3899 M - - -- - - 4 1 Hour Day 3 R e fe r e n c e fo r p o s it iv e and n e g a tive scores (2 4 , 48 and 72 h o u rs ): 1 . 16 CFR 15 0 0 .4 2 c. I l l u s t r a t e d G u i d e f o r G r a d i n g E y e I r r i t a t i o n by H a z a r d o u s S u b s ta n c e s . ( U .S . Government P rin tin g O f f i c e , Washington, D.C. 02402) bTime cle a r is time th a t eye was fre e o f a l l i r r i t a t i o n . C om p any Sanftheit. Does not contain Append! A , Stenderd Eye Ir r ita tio n Grading Seale' I . CORNEA A . O o a c lty - degree o f de n s ity (area m t t d e n t* .taken f o r reading) No o p a c i t y . . . . . . . .............} ........................... ......................................................................................... Sc tte re d 1 o r"d 1f fu s e 'a r e is " ^ op ac ity (o tte r than lig h t d u llin g o f normal l u i t e r ) , d e t a i l * o f i r l i c le a r ly v i s i b l e . . . . . . . . . . ................ 1 * E a s ily discernible trap lucent areas! d e ta ils o f 1 r 1 * s lig h tly Opalescent a re a s, no d e ta ils o f I r i s v is ib le , s ize o f pu p il 4 b a r e ly d i s c e r n i b l e ...,...................................................................................................................................... r t O paque, I r i s I n v i s i b l e ......................................................................................................................................... B . T o m area o f cornea Involved: (T o ta l area e x h ib itin g any o p a c ity , regardless o f degree) ," , One q u a rte r (o r le s s ! b u t n o t z e r o .................................................................................................... ' G re a te r than one q u a r te r , b u t le s s th a n h a l f ..................................................................... * G r e a te r than h a l f , b u t le s s than th re e q u a rte r s ............................................................ 3 G r e a te r than th re e q u a r te r s , up t o whole re a .................................................................. * Corneal Score2 : A X B X 5 (Ns 1 u b Score 80) C . S tlD D lIn g - (appearance o f p in p oin t roughe ning )** ,, n o s t i p p l i n g ................................................................................................................................................................................? One q u a rte r ( o r le s s ) b u t n o t z e r o ..................................................................................................... ' G r e a te r than one q u a r t e r , but l e t s than h a l f ..................................................................... ` G r e a te r than h a l f , b u t le s s than th re e q u a rte r s ................................................3 G re a te r than th re e q u a r te r s , up to whole a r e a ................................................................ * 0 . U lce ra tio n - (absence o f a gross patch o f corneal e p ith e liu m )** n n o u l c e r a t i o n ........................... .................................................................................................................................................. , # One q u a rte r ( o r le s s ) b u t n o t z e r o .................................................................................................. I G re a te r than one q u a r t e r , but le s s than h a l f ...................................................................... ` G re a te r than h a l f , b u t :l e s s than th re e q u a rte r s ............................................................ 3 G r e a te r than th re e q u a r te r s , up to whole .............................................................................. 4 I I . IRIS XT^le lu e s Norm al...........................................................................................................................................................................................u S lig h t deepening o f the rugae o r s lig h t hyperemia o f the c lrc u n c o m e a l b lood v e s s e ls ..................................................... .................................................................+ M arkedly deepened fo ld ) (above n o n a a l), co n ge stion , s w e llin g , clreumcorneal in je c tio n (any o r a ll o f these o r combination o f any th e re o f). I r i s :s t i l l reacting to lig h t (sluggish re a c tio n 1 s p o s i t i v e ) :............................................................................ ; ........................ ' No re a c tio n to l i g h t , hemorrhage, gross d estru c tion (eny o r a ll # # o f th e s e )................................... j ........................................ ...............................................................................................* I r i s Score2 : A X 5 (Maximum Score 10 ) A-l 5227-84 I ! I " A ^ R e d n e s s E (re fe rs to palpebral and b u lb a r co n ju n ctlva e excluding cornea and Ir is ) ,, V e s s e ls n o r m a l................................................................................... ................................. ....................................... * Some ve ss e ls d e f in i t e ly In je c te d aboven o r m a l . . . . . . . . . ......................................... ' D iffu s e , crimson re d , Ind ivid ua l vessels not e a s ily d is c e r n ib le .... 2 * D if f u s e beefy re d ........................................................................................................................................................ 3 B . Chewosis g An y*sw el 1 i n g ' a b o v e n o r ia i(in c lu d e sn i c t i t a t i n g membrane)..................................... 1 O b vio u s s w e llin g w ith jia r t le l e v e rs io n o f l i d s ...............................................................* S w e llin g w ith l i d s a b o u t h a lf c lo s e d ..............................................................................................3 . S w e llin g w ith l i d s morethan h a l f c lo s e d ........................................................................................4 C . Discharge n No d isc h a rg e ........................................................................................................ Any amount d i f f e r e n t fro m normal (do es n o t In c lu d e small amounts u observed I n In n e r csnjttus o f normal a n i m a l s ) .,................ ..................1 Discharge w ith m oistening o f the lid s and h a irs Ju s t adjacent to H d * . ....................................................... ....................................................................................a ...................................................................... Z Discharge w ith m oistening o f tte lid s and ha irs and considerable a rea aro< e y e ................................................................... 3 D . Necrosis o r u lc e ra tio n o f palpebral and bulbar conjunctlvae o r n i c t i t a t i n g msmprane . N o t p re s e n t................................................................................................................................................................................ , N e c ro s is p re s e n t........................................................................................................................................................... !J . U lc e r a tio n p re s e n t.................................................................................................................................................... " Conjunetlvae Score2 : (A 8 * 0 X 2 ttsiw m Score 20) i D r a l z e , J . H . 195 9. The W a t s ': o f C h s a lc a ls in F e e d s , D ru g s , and Cosm etics, p . S I . Asso ciatio n o f Food and Drug O ffic ia ls o f the .U n ite d S ta te s , A u s tin , T e ia s. 2T o t a l O r a lz e score I s th e s in o f t t e th re e scores ob tained (co rn ea . I r i s , conju nctlvae ). Score considered p o s itiv e under 16 CFR 1500.42 .................... N o t Included in O ra lze grading system, values assigned i f fin d in g present. S a n itize d . D o e s n o t contain T S C A Ciffi