Document 2jj895J963ZeEZ88ewddpkN1p

1c;c 0 FL)EI OFFICE ECY 7545 11rA,[)I'@C)14,V\'1 5 3 7 0 7 - 7 E,4 5 FINAL REPORT . Rog er G. Perkins, PhD 3M Toxicology Services Building 220-2E-02 St. Paul, MN 55144-1000 HWI Number: 40200470 Study Title: PCFA\PP/\LI 0 /Cr* PrimaryEye Irritation/Corrosion Study of T-5898 in Rabbits (OECD Guidelines) Signed: Steven-M- Glaza Date Study Di@ector .Acute Toxicology r c, r e F C@ P. F, 6 0 f@ 2 4 1 - 4 'i 1 t,/. IL "-)E L I L R Y: I i.,I c@; IV, A f,@ L' L V R i,i. I HWI Number: 40200470 Sample: T-5898 Acute Toxicology Steven M. Glaza Study Director Manager Steven R. Sorenson Study Coordinator Patricia Padgham In-lifeSupervisor Rose M. Bridge Report Supervisor Page 2 KEY PERSONNEL Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor CONTENTS Paqe Key Personnel 2 Objective 3 Test Material 3 Test System 3 Procedures 4 Summary of Results 6 Discussion 10 References 10 Appendix - Raw Data 11 HWI Number: 40200470 Sample: T-5898 Page 3 OBJECTIVE The objectiveof this studywas to assessthe relativelevel of irritation/ corrosion produced followinga single exposureof a test materialto one eye of albinorabbits.1 All proceduresused in this study are in compliancewith the Animal Welfare Act Regulations. In the opinion of the Sponsorand study director,the study did not unnecessarilyduplicateany previouswork. TEST MATERIAL Identification The test materialwas identifiedas T-5898 and describedas a clear, lightyellow liquid. Purity and Stability The Sponsorassumesresponsibilityfor purity and stabilitydeterminations (includingundertest conditions). Storage and Retention The test material was stored at room temperature. Any unused test material will be returnedto the Sponsorafter issuanceof the final report according to Hazleton Wisconsin (HWI) Standard Operating Procedure (SOP). Safety Precautions The test material handling procedureswere accordingto HWI SOPs and policies. TEST SYSTEM- Test Animal Adult albino rabbitsof the Hra:(NZW)SPFstrainwere procuredfrom HRP, Inc. and maintainedat the Hazleton Wisconsin facility at 3802 Packers Avenue, Madison, Wisconsin. Animal husbandry and housing at HWI comply with standards outlined in the "Guidefor the Care and Use of LaboratoryAnimals".2 The animals were individuallyhoused in screen-bottomcages in temperature-and humidity-controlledquarters, provided access to water ad libitum and a measured amount of Laboratory Rabbit Diet HF #5326, PMI Feeds, Inc., and held for an acclimationperiodof at least 7 days. The feed is routinelyanalyzed by the manufacturerfor nutritionalcomponentsand environmentalcontaminants. HWI Number: 40200470 Sample: T-5898 Page 4 Samples of the water are periodicallyanalyzedby HWI. There were no known contaminantsin the feed or water that would have interferedwith or affected the resultsof the study. Three female acclimatedanimals, weighing from 2,628 to 2,722 g, were selected and maintainedduring the study in the same manner as for the acclimation period. If variationsfrom the requiredtemperatureand humidityconditions existed, they were documented and considered to have had no adverse effect on the study outcome. The animals'eyes were examined on the day before test material administrationusing sodium fluoresceindye procedures. Only those animalswith no sign of ocular injury or irritationwere used. Animals were identifiedby animal number and correspondingear tag. Justificationfor Species Selection Historically,the New Zealand White albino rabbit has been the animal of choice based on its large orbit and nonpigmentediris. PROCEDURES. Pre2arationof Test Material The test materialwas administeredas received. The pH of the test material was determined to be 7.6. Treatment Each rabbit received0.1 mL of the undilutedtest material placed into the evertedlower lid of the right eye, with the left eye servingas the untreated control. The upper and lower lids were gently held togetherfor 1 second to prevent loss of material and then released. The eyes of the rabbits remained unflushed. Reason for Route of Administration Historically,the ocular route has been the route of choice based on the method of Draize.3 Observations The treatedeyes were observedfor ocular irritationat 1, 24, 48, 72, and 96 hours and Days 7 and 14 after treatment. Irritationwas graded and scored accordingto the Draize technique. Sodium fluoresceinexaminationswere used to aid in revealingpossiblecorneal injury at 72 hours and Days 7 and 14. HWI Number: 40200470 Sample: T-5898 Page 5 Animals were weighed just before test materialadministrationand at weekly intervalsthroughoutthe study. Termination At terminationof the experimentalphase, all animalswere designatedto be euthanized and discarded. StatisticalAnalyses No statisticalanalyseswere requiredby the protocol. Location of Raw Data, Records, and Final Report The raw data, records,and a copy of the final reportwill be retainedin the archives of HWI in accordance with HWI SOP. HWI Number: 40200470 Sample: T-5898 Page 6 SUMMARY OF RESULTS Test Animal: Albino Rabbits - Hra:(NZW)SPF Source: HRP, Inc., Kalamazoo,MI Date Animals Received: 02/17/94 ExperimentalStart Date: 02/24/94 ExperimentalTerminationDate: 03/10/94 Average Primary Eye IrritationScores* Observation Period Average Score 1 Hour 24 Hour 48 Hour 72 Hour 96 Hour Day 7 Day 14 24.3 26.7 15.0 10.3 7.3 4.3 0.0 The averageprimaryeye irritationscore*isthe total eye irritation score for all the animalsdivided by the number of animals (3) at each observationperiod. HWI Number: 40200470 Sample: T-5898 Page 7 Animal Number F49828u F49829t F49795u Table I IndividualEye IrritationStores Cornea A Iris c Conjunctivae E I Hour 1 1 11 2 2 2c 11 2b 3 2c 1 1 2 11 1 2b 2 2c Mean Total Score* 22.0 29.0 22.0 24.3 24 Hours F49828 1 1 1111 22bb 32 2idc 2304..00 F49829 1 F49795 1 3 1 11 .2b 3 3c 26.0 Mean 26.7 F49828 F49829 F49795 0 0 ij 2 ij 1 48 Hours 0 1 11 2b ii 2 0 0 2 2c 1 0 Mean 2.0 27.0 16.0 15.0 Cornea A - Degree of opacity B - Area of involvement Iris C - Degree of iridal irritation Conjunctivae D - Redness E - Chemosis F - Discharge Totalscore= (A x B x 5) + (C x 5) + [(D+ E + F) x 2]. b Blanching. c Clear discharge. d Purulent discharge. i Injected. j Cornealepithelialpeeling. t No pain responseafter test materialinstillation. u Excessivepawingat the treatedeye after test materialinstillation. HWI Number: 40200470 Sample: T-5898 Page 8 Animal Number F49828 F49829 F49795 Table 1 (Continued) IndividualEye IrritationScores Cornea A Iris c Conjunctivae D E 72 Hours 0 0 1 1 ij 1 0 1 0 0 il 2b 1 ic 0 2 1 0 Mean Total Score* 2.0 18.0 11.0 10.3 96 Hours F49828 0 0 0 F49829 1 1 0 F49795 1 1 0 0 0 2 1 .2 1 0 0.0 0 11.0 0 11.0 Mean 7.3 F49828 F49829 F49795 0 0 0 0 ij 1 Cornea A - Degree of opacity B - Area of involvement Day 7 0 0 0 0 1 0 0 2 1 Mean Iris C - Degree of iridal irritation Totalscore= (AxBx5) + (Cx5) + [(D+E+ b Blanching. c Clear discharge. i Injected. j Corneal epithelialpeeling. F) x2]. 0 0.0 0 2.0 0 11.0 4.3 Conian(z-tiv-ae B - Redness E - Chemosis F - Discharge HWI Number: 40200470 Sample: T-5898 Page 9 Animal Number F49828 F49829 F49795 Table I (Continued) IndividualEye IrritationScores Cornea B Iris c Conjunctivae D E Day 14 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Mean Total Score* 0.0 0.0 0.0 0.0 Cornea A - Degree of opacity B - Area of involvement Iris C - Degree of iridal irritation Total score= (A x B x 5) + (C x 5) + [(D+ E + F) x 2]. Conjunctivae D - Redness E - Chemosis F - Discharge Table-2 Sodium Fluorescein Examination Animal Observation Period Number Sex Preinitiation 72 Hour Dav 7 Day 14 F49828 F NEG NEG NEG NEG F49829 F NEG NEG NEG NEG F49795 F NEG POS (5%) POS(5%) NEG NEG Negative stain retention. POS Positive stain retention(areaof cornea involved). HWI Number: 40200470 Sample: T-5898 Page 10 DISCUSSION The test material,T-5898,when evaluatedfor its primaryeye irritation potentialin rabbits,producedcornealand iridal involvementand moderate to severeconjunctivalirritation. All treatedeyes had returnedto a normal appearance by Day 14 after treatment. REFERENCES 1. "Acute Eye Irritation/Corrosion," Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 405 (adoptedMay 12, 1981). 2. NIH PublicationNo. 86-23 (revised1985). 3. Draize, J. H., "Eye Mucosa," In: Appraisa7 of the Safety of Chemicals in Foods, Drugs and Cosmetics - Dermal Toxicity, Association of Food and Drug Officialsof the U.S.,pp. 49-50 (1959). HWI Number: 40200470 Sample: T-5898 APPENDIX Raw Data Page 11 PERSONNEL SIGNATURE SHEET ACUTE TOXICOLOGY HWI: LOQ@4@ Name Rose M. Bridge Job Title Report Supervisor Signature Anthony Cass Cindy J. Cary, DVM Lab Animal Technician Lab Animal Veterinarian Crt i@. LT Donna J. Clemons, DVM, MS Lab Animal Veterinarian John A. Disch Lab Animal Caretaker Charles W. Fritz Lab Animal Technician 640 14 Kari Garfoot Lab Animal Technician Steven M. Glaza Manager Kevin Grossman Lab Animal Caretaker Jeff Hicks Lab Animal Technician Sharen L. Howery Research Assistant Wayne A. Madison Supervisor Doug McConnell Lab Animal Technician Eileen McConnell Bud McDonald Albert Oleson Patricia Padgham Staff Assistant Study Coordinator Lab Animal Caretaker In-lifeSupervisor e-@:"Y' 0 .1900 Steven R. Sorenson Study Coordinator Annette R. Turner Staff Assistant Tamra L. Walker Staff Assistant Lana M. Weeden Staff Assistant Initials @-o@o aye@@ r (G2/10-06-93) HWI No.: i4t-)2jODL12t) TEST KATERIAL ADNINISTRATION RECORD Test Naterial: -t-- See L@S Physical Description: r-A k:Agk2eL--JC--.,Wi- pH Result: 7-to with Corning pH Neter No. pH was determined on: undiluted material / AA U - Unable to determine pH due to ma Storage conditionsof test material: P-CY:!)NA 05510 dilution of n tiA % tiAlivA Approxircmoaaitt@elyyH5cmlm@nfno Lotttee@ssttmmaa@tteerrii@aallinstillation2 dropsof 0.5% Dprpr@pdOrDpoaXariraRc@aainneeHCI (ODDhhtthh@aaiinneeL@ot I were placed on the corneal surface of _ eye(s) of each rabbit.Tech.@ Group&g Dose:-Qj-mL/-&Iag (Ljg-mL equivalent) Time: From_Li.A%a_Toja.-Q2_ Unflushed &JG Flushed: tjia secondsaftertest materialinstillationt,he test eye of each animal was flushedwith t@,IA ML of Iukewam tap water for b.)A seconds / minutes. Time: From__NIQL_To_&Ia._ Group _ Dos _g (-_--pLequivalentT)ime:FroitL_To_ Unflushed Flushed: seconds after test mate stillationt,he test eye of each animal was flushedwith _ mL o m tap water for _ seconds / minutes. Time: From_ vlDoswaes administeredusing a 1-mL disposable syringe. &)a Dose was administeredusing a "A -AL glass syringe. &A Dose was weighed into and administeredusing a weighing paper. &)A,Dosewas placed directlyon the cornealsurfaceof the right eye. The eyelids were releasedimediately without forced blinkingor manipulation. Dose was placed into the everted lower lid of the right eye. The upper and lower lids were gently held together for one second and then released. &),-Oqther: tJA DosingTechnician/Date:4.rCrkc Time of 1-hour scores: is.6q L 9-.14-94 Technician/Date: cir 1 2-p-l-cly NA Not applicable.DEjtry f-rror ac (E8/12-09-92) Final data review by/Date: -0Y1- HWI No.: BODYWEIGHT/ TRUTMENT EFFECTRECORD Test Material: Species/SourcSetrain/Location: Rabbit/Hra:(NZW)SPF/I\Al Date AnimalsReceived: 2--1-) 12- -')-C-lCL5 Initiatedin Room Number: I Animal Number 6roup PL-APA? Pl@ qpo-g Initial Pain Response Sex SF* Following Animal Body Weights (9) Time:13:41 Dosing Initiation Day 7 Day 14 Day 21 c ? L,1,4'g @ (.aI*' 'g-@gg 2q go 7q 15LB, Technician C)LC Date Used Isca.10 Sodium fluoresceinexamination. NEG Negative. POS Positive. NA Not applicable. V Vocalization. E Excessive pawing of treated eye. N None. OL C- kg2qfs, OLC 1 csg,0w4-c-kv 926" 2.S -0@L4 On the day of treatment,all animals were weighed and appeared normal before test material administration. Technician/Date: CLc /@2-94-9q Survivinganimalswere designated for sacrificeand discard. Technician/Date: -c-?@,L (E2/12-09-92) Final data review by/Date: HWI No.: PRIMARY EYE IRRITATION OBSERVATIONS Test Material: Group: LIA Test eye: -li_qht Observation Period: Animal Number F44 P824B pf@Iq (4-7QS Locationof Corneal Lesions Cornea Opacity Area Iris Redness Conjunctivae Chemosis 3 Discharge 9 C- 9 C- gc Sodium Fluorescein exam ti A riA ti A Technician: Date: OLra-9,1-9 Li Eye IrritationScore: Calculated by/Date: Verified by/Date: O.C -7,Y KA Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Hair loss aroundthe eye. F Possiblenecroticareas. G Unable to visualizedue to severe conjunctivalswelling. H No reactionto light. I Injected. J Cornealepithelialpeeling. K Cornealepithelialpitting. L Corneal'edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualizedue to severe corneal opacity. S Granulationscar tissue. POS Positivestain retention. NEG Negative stain retention. (E3/07-15-92) Final data review by/Date: -,7hz HWI No.: L6=mq2c) PRIMARY EYE IRRITATION OBSERVATIONS Test Material: Group: LIA Test eye: __Rilht Animal Number observation Period: iE@4 P82.8 Location of Corneal Lesions Cornea Opacity Area Iris Redness 2_f& Conjunctivae Chemosis 2@- D ischarge ic oedi:u:mFluorescein exam, ti 2.P "I@6. H 0".g"c 13 Ilia Technician: Date: 2- - 2-S -c@-4 Eye IrritationScore: 2-Lp.-i Calculated by/Date: L-.,i 2--2.,5-ci4 Verifiedby/Date: ;9,V NA Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Hair loss around the eye. F Possiblenecroticareas. G Unable to visualizedue to severe conjunctivalswelling. H No reactionto light. I Injected. J Corneal epithelialpeeling. K Corneal epithelialpitting. L Corneal edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualizedue to severe corneal opacity. S Granulationscar tissue. POS Positivestain retention. NEG Negative stain retention. (E3/07-15-92) Final data review by/Date: ,7h4 HWI No.: qn2rY--@q-JC) PRIMARYEYE IRRITATIONOBSERVATIONS Test Material: Group: biA Test eye: __Right Animal Number Observation Period: F4 @ZZ A4,,,.e Location of Corneal Lesions Cornea Iris Opacity Area 0 Redness Conjunctivae Chemosis Discharge Sodium Fluorescein exam Alf X z Al-4 Technician: Date: Eye IrritationScore: Calculated by/Date: Verified by/Date: ,771 CLC 13-3-qq NA Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Hair loss around the eye. F Possible necrotic areas. G Unable to visualize due to severe conjunctival swelling. H No reaction to light. I Injected. J Corneal epithelial peeling. K Corneal-epithelialpitting. L Corneal edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualize due to severe corneal opacity. S Granulation scar tissue. POS Positive stain retention. NEG Negative stain retention. (E3/07-15-92) Final data review by/Date: HWI No.: L4n?-rYNqa 0 PRIMRY EYE IRRITATIOONBSERVATIONS Test Material: Group: LIA F@p F@ Test eye: -Riqht Animal Number Observation Period: 1:::@A-4-.-P824B- Locationof Corneal Lesions Cornea Opacity Area Iris Redness Conjunctivae Chemosis Discharge Sodium Fluorescein exam, Ile 0 Technician: Date: '1-71 M Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Hair loss around the eye. F Possiblenecroticareas. G Unable to visualizedue to severe conjunctivalswelling. H No reactionto light. I Injected. Eye Irritation Score: Calculated by/Date: Verified by/Date: ZO. .721 clir 3-3-q!i J Cornealepithelialpeeling. K Cornealepithelialpitting. L Corneal edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualizedue to severe corneal opacity. S Granulationscar tissue. POS Positivestain retention. NEG Negativestain retention. (E3/07-15-92) Final data review by/Date: iL--l LQLL HWI No.: qn2fy,@q2c) PRIMRY EYE IRRITATIOONBSERVATIONS Test Material: Group: biA Test eye: --Ij-qht Observation Period: f.Ag AnimalNumber iE@q Location of Corneal Lesions Cornea Opacity Area Iris 0 Redness Conjunctiva-e n Chemosis 0 Discharge e5 Sodium Fluoresceinexam AJA 0 2-1 0 I /-.Ai . 2-1 e> Technician: A(f--) Date: 2-2 -a Eye IrritatioSncore: -7..3 Calculatedby/Date: I/ 2-.;;-SC)@i Verifiedby/Date: m C' 1-;---39,1 NA Not applicable. A Petitehemorrhaging. B Blanching. C Clear discharge. D Purulentdischarge. E Hair loss aroundthe eye. F Possiblenecroticareas. G Unableto visualizedue to severeconjunctivaslwelling. H No reactionto light. I Injected. J Cornealepithelialpeeling. K Cornealepitheliaplitting. L Corneal edema. N Hypopyon. N Cornealneovascularization. P Pannus. R Unableto visualizedue to severecornealopacity. S Granulationscartissue. POS Positivestainretention. NEG Negativestainretention. (E3/07-15-92) Final data reviewby/Date: cxc- 3 -11 HWI No.: qn2fy'@q- IC) Test Material: Group: --LZA PRIKARY EYE IRRITATION OBSERVATIONS f@@q F@, Test eye: __Ri_qht Animal Number Observation Period: nato A2,B C)PJ2-q Locationof Corneal Lesions Cornea Opacity Area Iris Redness 0 Conjunctivae Chemosis 0 Discharge Sodium Fluorescein exam Technician: Date: CLC !3-3-9q -i s 11/0 0 1 0 N)f(-r pos/o- Eye IrritationScore: 4.3 Calculated by/Date: Cie 3-3-9,f Verified by/Date: IL--aL,?@ KA Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Hair lossaround the eye. F -Possiblenecroticareas. G Unable to visualizedue to severe conjunctivalswelling. H No reactionto light. I Injected. J Cornealepithelialpeeling. K Cornealepithelialpitting. L Corneal edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualizedue to severe corneal opacity. S Granulationscar tissue. POS Positivestain retention. NEG Negative stain retention. (E3/07-15-92) Final data review by/Date: HWI No.: L-k)7-fY)q--M PRIKARYEYE IRRITATIOONBSERVATIONS Test Material: Group: bl4 Animal Number Observation Period: P4 tSaL4 14 Test eye: ___Ri$Lht Location of Corneal Lesions Cornea (Doo(:@oo Opacity Area Iris 6 Redness 0 0 Conjunctivae Chemosis 0 Discharge 0 FSodim Fluoresceinexam Technician: Date: /L/ In -C Eye IrritationScore: o.o Calculated by/Date: Verified by/Date: /C:Z) oc- 13-it-91( NA Not applicable. A Petite hemorrhaging. B Blanching. C Clear discharge. D Purulent discharge. E Ha-irloss around the eye. F Possiblenecroticareas. G Unable to visualizedue to severe conjunctivalswelling. H No reactionto light. I Injected. J Corneal epithelialpeeling. K Corneal epithelialpitting. L Corneal edema. N Hypopyon. N Corneal neovascularization. P Pannus. R Unable to visualizedue to severe corneal opacity. S Granulationscar tissue. POS Positivestain retention. NEG Negative stain retention. (E3/07-15-92) Final data review by/Date: ar_ 13 -11-91-f HWI No.: 402-900q-70 SCALEFORSCORINGOMM LESIONS (DRAIZE TECHNIQLIE) (1) Cornea (A) Opacity- Degreeof density (areamost dense taken for reading) No opacity.........................................................0................. Scatteredor diffusearea.detailsof irisclearlyvisibl.e......................1.*........ Easilydiscernibletranslucentareas.detailsof iris slightlyobscured..............2.*.... Opalescentareas,no detailsof iris visible,size of pupil barelydiscernibl.e........3.*.. Opaque,iris invisibl.e................................................4.*................ (B) Area of Cornea Involved One-quarter(or less),.butnot zero........................................I............... Greaterthan one-quarter,but less than half.................................2.............. Greaterthan half, but less than three-quarter.s..............................3............ Greaterthaq three-quartersup to whole area.................................4............. A x B x 5 Total Maximum - 80 (2)Iris (A) Values Nonm I.............................................................................. 0 Folds above normal. congestion. swelling. circumcorneal Injection (any or all of or combinationof any thereof)iris is stillreactingto light(sluggishreactionis positive).........................................................I.*................ No reactionto light,hemorrhage,gross destruction(anyor all of these).............2*.... Ax5 Total Maximum - 10 (3) ConJunctivae (A) Redness (refersto palpebraland bulbarconjunctivaeexcludingcorneaand iris) Vessels normal.......................................................0 ................ Vessels definitelyinjectedabove normal....................................I.............. More diffuse,deeper crimsonred. individualvesselsnot easilydiscernibl.e ..........2.*... Diffusebeefy red....................................................3.*................ (8)Chemosis No swelling.........................................................0 ................ Any swellingabove normal (includesnictitatingmembrane)........................1......... Obviousswellingwith partialeversionof the lids.............................2.* .......... Swellingwith lidsabout half closed.......................................3.*.............. Swellingwith lidsabout half closed to completelyclosed........................4.*........ (C) Discharge No discharge........................................................0................. Any amount differentfrom normal (doesnot includesmall amounts observed in inner canthus of normal animals)..............................................I................. Dischargewith moisteningof the lidsand hairs Just adjacentto the lids.............2.... Dischargewith moisteningof the lids and hairs, and considerablearea around the eye....3. Score (A + B + C) x 2 Total Maximum - 20 The totalscore for the eye is the sum of all scoresobtainedfor the cornea,iris.and conjunctivae. Indicatesa positiveeffect. (FHSAInterpretation) (E4/01-06-91)