Document yr4YM238MJR6LpDK4KEM1Dp1D

Experiment No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: Acute Ocular Irritation Test with T-3493 in Albino Rabbits /Ume-ojp 0884EB0008 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota January 3, 1984 to January 10, 1984 O- * D. M. Markoe, Jr., BS Toxicologist Study Director Date C '- vjl-a - K.' D. O'Malley, B Senior Toxicologist Acute Toxicology IhikL Date dc: M. T. Case K. L. Ebbens W. C. McCormick 005207 1. 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-3493 is minimally irritating (2.0/110.0) to the eye of the female albino rabbit. Minimal conjunctivitis was noted at the one hour evaluation and subsided by the two day evaluation. Corneal opacity and iritis were not produced during the study. Introduction The objective of this study was to determine the acute ocular irritation properties of T-3493 when instilled into the eye of female albino rabbits. This study is not regulted by the Food and Drug Administration's Good Laboratory Practice Regulation of 1978, although the standard operating procedures of this laboratory adhere to the general principles of this regulation. The raw data generated by the Study Director and the final report are stored in the conducting laboratory1s archives. 005208 Method and Results a Young albino rabbits of the New Zealand breed-- were used to evaluate the ocular irritating properties of the test article. b modeled after that of Draize ^ t 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 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 T- Hazleton Dutchland, Inc., Denver, PA -- Draize: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1965). 005209 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. 005210 Table 1 Eye Irritation Test - Albino Rabbits Treatment Procedure Test Article Number of Animals Evaluated Form Administered Quantity of Test Article Administered Contact Period (seconds) Volume Evaluation Time of Wash Post Dose (tap water) Administration T-3493 6 paste 0.1 gm unlimited none 1 Hour, 1, 2, 3 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 Draize _____________________ Description_____________________________ Grade Redness (A) Redness (refers to palpebral conjunctiva only). 1 Vessels definitely injected above normal. More diffuse, deeper crimson red, individual 2 vessels not easily discernible. Diffuse beefy red. 3 Chemosis (B) Any swelling above normal (included nictitating membrane). 1 Obvious swelling with partial eversion of the lids. 2 Swelling with lids about half-closed. ' 3 Swelling with lids abouthalf-closed tocompletely closed. 4 Discharge (C) Any amount different from normal (Does not include small 1 amount observed in inner canthus of normal animals). Discharge with moistening of the lids and hairs just 2 adjacent to the lids. Discharge with moistening of the lids and hairs and 3 considerable area around eye. 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. Easily discernible translucent areas, details of iris slightly obscured. Opalescent areas, no details of iris visible, size of pupil barely discernible. Opaque, iris invisible. Area of Cornea Involved (B) One quarter (or less) but not zero. Greater than one-quarter, but less than one-half. Greater than one-half, but less than three-quarters. Greater than three-quarters, up to whole area. 1 2 3 4 1 2 3 4 Score equals A x B x 5 Total maximum = 80 Iris Values (A) Folds above normal, congestion, swelling, 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 destruction (any or all of these). 1 2 Score equals A x 5 Total maximum = 1 0 Notes The maximum total score is the sum of all scores obtained for the cornea, iris and conjunctiva. 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 Severely Irritating Extremely Irritating Range 0.0 - 0.5 >0.5 - 2.5 >2.5 - 15.0 >15.0 - 25.0 >25.0 - 50.0 >50.0 - 80.0 >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 is 20 but < 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 seven days must be 30 for 60% or more of the animals. Also, mean seven day score must be _< 40. If seven day mean score is jC 40 but < 60% of the animals show scores <_ 30, then no animal among those showing scores > 30 can exceed a score of 60 if rating is to be maintained; otherwise, raise rating one level. 005213 TABLE 4 EYE IRRITATION TEST - ALBINO RABBITS BEST COPY AVAILABLE Examination Tissue Period Cornea(D-A) 1 Hour Iris Conjunctiva (RSD) Total Cornea(D-A) 1 Day Iris Conjunctiva (RSD) Total Cornea(D-A) 2 Days Iris Conjunctiva (RSD) Total Cornea(D-A) 3 Days Iris Conjunctiva (RSD) Total Cornea(D-A) 7 Days Iris Conjunctiva (RSD) Total 3B2058 0 0 2(1-0-0) 2 0. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Key: Cornea: D=Density -- Conjunctiva: R=Redness with T-3493 3B2061 0 RESULTS ANIMAL NUMBERS 3B2064 0 00 4 (2-0-0) 4(2-0-0) '4 4 0 0 2(1-0-0) 2 0 0 0 0 0 0 0 0 0 0 0 0 00 00 00 00 00 00 00 00 3B2067 0 0 2(1-0-0) 2 0 0 0 0 0 0 0 0 0 0 0 0 3B2057 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 00 00 1 3B2060 0 0 0 0 Means 0.0 0.0 2.0 2.0 0 0.0 0 0.0 0 0.3 0 0.3 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 0.0 0.0 0.0 '1 i 005214 BEST COPY AVAILABLE Riker Experiment No.:_ APPENDIX I PROTOCOL JE ST : Acute Ocular Irritation Test _____________________ ______________________________________ _ SPONSOR: 3M O n v ie rc i s l C hei.5c= U ___________________ ________________________________ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE:. Z-1-J2_______________________________________________________________________ CONTROL ARTICLE: __________________________________________________________ !_____________ PR O PO SED STARTING/CpMPLETION DATE OF T E S T :.. 'jJLl_ __ _________________________________ TEST SYSTEM: Female New Zealand White Albino Rabbits SOURCE: Li ' '.Hr./. . . ;v, f c L. . -k ; A OBJECTIVE: The objective of this test will be to determine the irritation potential of the test article to the ocular tissues (cornea, iris and conjunctiva) o f ___ L_... albino rabbits. Rabbits were selected as the test system for their sensitivity to irritants, historical use, ease of handling and general availability. METHOD: The animals will be housed in standard wire-mesh cages in temperature and humidity controlled rooms with foo di and water offered ad libitum. Each animal will be assigned a numbered ear tag which will correspond to a card affixed to the outside of the cage. The test article will be instilled into the conjunctival sac of the right eye at a dose of __ l____ with the contralateral eye pf each animal serving as a control. A t ____________:___________ hours a n d ____ ___ __________ :----------days (additional scoring intervals may be added to further characterize the ocular reactions), the tissues will be examined and graded for irritation and injury according to a standard scoring system of Draize ef a/. After completion of the test, the scores will be analyzed, and a descriptive eye irritation rating assigned to the test article. Eye examinations may be carried out with the aid of sodium fluorescein. If deemed necessary by the study director, washed eye procedures entailing a 5 and 30 second contact period with a * } ' f wash over a ' .. period will be conducted using 3 animals per procedure. All raw data generated by the study director and the final report will be stored in the Riker Laboratories' Archive, St. Paul, Minnesota. Purina Rabbit Chow, Ralston-Purina, St. Louis, Missouri b Draise: Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics (1965) Published by the Editorial Committee of The Association of Food and Drug Officials of the United States. ' io ' Sponsor A 'A/'.' Date" Study Director DliC /.ill. Date Form 19171-7-A-PWO 005215 APPENDIX II Principal participating personnel Involved in the Study Name D. M. Markoe, Jr., BS K. L. Ebbens, BS K. D. O'Malley, BS G. C. pecore _______________________________ Function Toxicologist Study Director Supervisor Toxicology Testing Senior Toxicologist Acute Toxicology Supervisor Animal Laboratory 005216 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. 005217 11. APPENDIX IV .Quality 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. 005218