Document Ra1nOX0XKbYRXMJXGB8XMxqnB

Experiment No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: Acute Ocular Irritation Test with T-3494 in Albino Rabbits 0884EBOOll Safety Evaluation Lab.orato-r'y'.,@* Riker Laboratories, Inc. St. Paul, Minnesota January 3, 1984 to January 10, 1984 D. M. Markoe, Jr.,*BS Toxicologist Study Director iluc-rm- Date K.' D. O'Malley,"-Bs Senior Toxicologist Acute Toxicology bate dc: M. T. Case K. L. Ebbens F. D. Griffith W, Ce McCormick Summary The results of the acute ocular irritation test conducted from January 3, 1984 to January 10, 1984 at Riker Laboratories, Inc., St. Paul, Minnesota indicate that T-3494 is minimally irritating (3.3/110.0) to the eye of the female albino rabbit. Neither corneal opacity nor iritis were produced during the study. Minimal conjunctivitis was noted at the one hour evaluation and subsided by the two day evaluation. Introduction The objective of this study was to determine the acute ocular irritation properties of T-3494 when instilled into the eye of female albino rabbits. This study is not regulated by the Food and Drug Administration's Good LaboratoryPracticeRegulation of 1978, although the standard operating procedures of this laboratoryadhere to the general principles of this regulation. The raw data generated by-the Study Director and the final report are stored in the conducting laboratory'sarchives. 2 Method and Results Young albino rabbits of the New Zealand breeg were used to evaluate the ocular irritating properties of the test article. b modeled after that of Draize et al=. The test method was The test article was instilled into the conjunctival sac of the right eye of each rabbit according to the treatment procedure presented in Table 1 with the left eye of each animal serving as a control. At each scoring interval, the cornea, iris and palpebral conjunctiva were examined and graded for irritation and injury according to a standard scoring b system . The maximum possible score at any one examination and scoring period 110 points, which indicates maximal irritation and damage to all three ocular tissues (cornea, iris, conjunctiva) while a score of zero indicates no irritation (Table 2). In this.scoring system, special emphasis is placed upon irritation or damage to the cornea, while less emphasis is placed upon damage to the iris and conjunctiva. After completion of the test, the scores were analyzed, and a descriptive eye irritation rating was assigned to the test article. The criteria used for assignment of the descriptive rating were the frequency, the extent and the persistence of irritation or damage which occurred to the three ocular tissues (Table 3). The individual results are presented in Table 4. a Hazleton Dutchland Inc., Denver, PA Draize: Appraisal'of the Safety of Chemicals in Ebods, Drugs and Cosmetics (1965). 3. The rating is arrived at by selecting the maximum mean irritation score at one hour, one, two or three days after instillation. If the rate of dissipation of injury does not meet the requirements defined for the descriptive rating appropriate for a particular numerical score, the descriptive rating is raised by one or more levels. The rating system is presented in Table 3. The protocol, principal personnel involved in the study, composition characteristics and Quality Assurance statement are contained in Appendices I IV. Table 1 Eye Irritation Test - Albino Rabbits Treatment Procedure Test Article Number of Animals Evaluated Pbrm Administered T-3494 6 solid Quantity of Test Article Administered 0.1 gm Contact Period (seconds) volume of Wash (tap water) Evaluation Post Dose Administrat unlimited none 1 Hour, 1, 2 and 7 Days 5. Table 2 Eye Irritation Test - Albino Rabbits Scale of Weighted Scores. for Grading the Severity of Ocular Lesions Ocular Tissues Conjunctiva Description Redness (A) Redness (refers to palpebral conjunctiva only). Vessels definitely injected above normal. More diffuse, deeper crimson red, individual vessels not easily discernible. Diffuse beefy red. Chemosis (B) Any swelling above normal (included nictitating membrane). obvious swelling with partial eversion of the lids. Swelling with lids about half-closed. Swelling with lids about.half-closed to completely closed. Discharge (C) Any amount different from normal (Does not include small amount observed in inner canthus of normal animals). Discharge with moistening of the lids and hairs just adjacent to the lids. Discharge with moistening of the lids and hairs and considerable area around eye. Draize Grade 1 2 3 1 2 3 4 1 2 3 Score (A + B + C) x 2 Total maximum = 20 Cornea opacity (A) opacity - Degree of density (area which is most dense is taken for reading). Scattered or diffuse area, details of iris clearly visible. 1 Easily discernible translucent areas, details of 2 iris slightly obscured. Opalescent areas, no details of iris visible, size of 3 pupil barely discernible, opaque, iris invisible. 4 Area of Cornea involved (B) one quarter (or less) but not zero. 1 Greater than one-quarter, but less than one-half 2 Greater than one-half, but less than three-quarters. 3 Greater than three-quarters, up to whole area. 4 Score equals A x B x 5 Total maximum = 80 iris values (A) Folds above normal, congestion, swelling, 1 circumcorneal injection (any.or all of these or combination of any thereof), iris still reacting to light (sluggish reaction is positive). No reaction to light, hemorrhage, gross 2 destruction (any or all of these). Score equals A x 5 Total maximum = 10 Mote: The maximum total score is the sum of all scores obtained for the Table 3 Eye irritation Test Albino Rabbits Classification of Test Materials Based on Eye Irritation Properties 6.- Rating Non-Irritating Practically Non-Irritating Minimally Irritating Mildly Irritating Moderately Irritating Range 0.0 - 0.5 >0.5 - 2.5 >2.5 - 15.0 >15.0 - 25.0 >25.0 - 50.0 Severely Irritating >50.0 80.0 Extremely Irritating >80.0 110.0 Definition To maintain this rating, all scores by the one day reading must be zero; otherwise, increase rating one level. To maintain this rating, all scores by the one day reading must be zero; otherwise, increase rating one level. To maintain this rating, all scores by the three day reading must be zero; otherwise, increase rating one level. To maintain this rating, all scores by the seven day reading must be zero; otherwise, increase rating one level. To maintain this,rating, scores by seven days must be < 10 for 60% or more of the animals. Also, mean seven day score must be < 20. If seven day mean score ii < 20 bu@-< 60% of animals show scores < 10, then no animal among those showing scores > 10 can exceed a score of 30 if rating is to be maintained; otherwise raise rating one level. To maintain this rating, scores by sevei days must be < 30 for 60% or more of the animals. Also, mean seven day scor must be < 40. If seven day mean score < 40 but@-< 60% of the animals show scores < 30, then no animal among thosf showing scores > 30 can exceed a score of 60 if rating is to be maintained; otherwise, raise rating one level. TABLE 4 EYE IRRITATION TEST - ALBINO RABBITS with T-3494 Examination Tissue Period Cornea(D-A) 1 Hour iris Conjunctiva (RSD) Total Cornea(D-A) rris 1 Day Conjunctiva (RSD) Cornea(D-A) Total 2 Days rris 6onjunctiva (RSD) To%.a Cornea(D-A) rris Conjunctiva (RSD) cornea (D-A) rris 3 Days Total 7 Dayjg Conjunctiva (RSD) Too'-6al --3B2037 0 0 4(2-0-0) 4 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 3B2036 0 RESULTS ANIMAL -NUMBM 3B2035 0 0 0 4(2-0-0) 4(2-0-0) 4 4 0 0 2(1-0-0) 2 0 0 0 0 0 0 2(1-0-0) 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3B2040 0 -7 3B2039 0 0 0 2(1-0-0) 4(2-0-0) 2 4 3B2038 0 0 2(1-0-0) 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 APPENDIX I PROTOCOL RikerExperiment No.: TEST: Acute Ocular IrritatiToenst SPONSOR: 3M CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories,Inc.,St.Paul, Minnesota TEST ARTICLE: T--7,4t)4 CONTROL ARTICLE: PROPOSED STARTING/COMPLETION DATE OF TEST: TEST SYSTEM: Female New Zealand White Albino Rabbits SOURCE: Division OBJECTIVE: METHOD: The objectiveof thistestwillbe to determine the irritatipoontentialof the testarticleto the ocularCISSL (cornea,irisand conjunctiva)of albiriorabbits.Rabbits were selected as the testsystf fortheirsensitivittyo irritanthsi,storicaulse, ease of handlingand general availability. The animals willbe housed in standard wire-mesh cages In temperature and humiditycontrol rooms with fooda-and water offeredad libitum.Each animal willbe assigned a numbered ear which willcorrespond to a card affixedto the ..Idoef the c-a-a.Teh.e testarticlewillbe Instilled the conjunctivalsac of the righteye at a dose with the.con ralektera-leyeof each an! serving as a control.At hours and c (additionaslcoringintervalsmay be added to furthercharacterizethe ocularreacflons)t,he tissues be examined and graded for irritatiaond injuryaccording to a standard scoring system of Dr et al!2.Aftercompletion of the test,the scores willbe analyzed, and a descriptiveye irritatiro.n assigned to the testarticleE.ye examinations may be carriedout with the aid of sodium ftuores Ifdeemed necessary by the,@@dy directorw,ashed en. Rmc ?dures entailinga 5 and 30 se contact periodwith a ------- wash over a periodwillbe conducted 3 animals per procedure. AJI raw data generated by the study directorand the finalreportvv stored'inthe Riker Laboratories'Archive,St.Paul,Minnesota. A Pudna Rabbit Chow, Ralston-Pudna, St.Louis,Missouri Draise: Appraisalof the Safetyof Chemicals in Foods, Drugs, and Cosmetics (1965) Published by the EditorialCommittee of The Associationof Food and Drug Officials of the United States. Sponsor Dite Study Director 9. APPENDIX 11 Principal Participating Personnel involved in the StuLy blame D. M. Markoe, Jr., BS K. L. Ebbens, BS X. D. O'Malley, BS G. C. Pecore Function Toxicologist Study Director Supervisor Toxicology Testing senior Toxicologist Acute Toxicology Supervisor Animal Laboratory 10. APPENDIX III Composition Characteristics This study is not regulated by the Good Laboratory Practice Act of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. APPENDIX IV Ouality Assurance Statement This study is not officially regulated by the Good Laboratory PrActice Regulation of 1978, and therefore a statement signed and prepared by the Compliance Audit department is not applicable. The standard operating procedures of this laboratory does adhere to the general principles of this regulation. The Compliance Audit department does inspect different significant phases for studies underway in the Acute Toxicology Laboratory on a recurring cycle, and the facilities are examined on a three month schedule. in addition a select number of Research & Development studies are routinely picked at random from the Archives by the Compliance Audit department for review.