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Experiment Mo.: Conducted At: Reviewed By: A ftlX -O H lM Primary Skin Irritation Test with T-3371 in Albino Rabbits 0883EB0079 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota March 1, 1983 to March 17, 1983 *7^ - -t. D. M. Markoe, J r ., BS ' Toxicologist Study Director v / ? c Aq Date YY g*-c y ^ A ,, o (u .' K. D. O 'Malley, BS Senior Toxicologist Acute Toxicology Date dc: M. T. Case K. L. Ebbens F. D. Griffith W. C . McCormi ck 000097 Summary The results of the ICAO skin irritation test conducted from March 1, 1983 to March 17,1983 at Riker Laboratories, In c ., St. Paul, Minnesota indicate that T-3371 produced irreversible tissue damage to the 6kin of female albino rabbits following a four hour, a one hour, and a three minute contact period. Moderate erythema and edema, as well as, chemical burn, eschar and necrosis were produced following all three contact periods. An endpoint, as required by ICAO, was not achieved due to the extreme irritation following each contact period. Introduction The objective of this study was to determine the ICAO skin irritation potential of T-3371 to the skin of female albino rabbits. This study is not regulated 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 laboratory's archives. 2. Method and Results Young albino rabbits of the New Zealand breech were used in the evaluation of the primary skin irritating properties of the test article. The test procedure was modeled after that of Draize _et al--. One day prior to the application of the test article, the hair was clipped from the back and flanks of each rabbit and two test sites selected lateral to the midline of the back approximately ten centimeters apart. Die test article (0 .5 g) was applied to each of the test sites on each rabbit and immediately covered with two-inch square gauzepatches. The patches, which were placed directly over the test sites, were secured with gauze wrap. The trunk of each animal was then wrapped with impervious plastic sheeting--c which held the patches in position during either a four hour, one hour or three minuted-- exposure period. At the end of the exposure period, the plastic wrappings, patches, and all residual test article were removed--e. One, 24 and 48 hours after removal of the test article, the test sites were examined for irreversible damage and scored separately for erythema and edema on a graded scale of 0 - 4 (Table 1 ). The length of the exposure period is reduced until an endpoint of no irreversible damage is reached, if possible. The results are presented in Tables 2-4. The protocol, principal personnel involved in the study, composition characteristics and Quality Assurance statement are contained in Appendices I - IV . ^aHazleton Dutchland, In c ., Denver, PA --Draize: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics ' --c (1109x6 5). 12 x .002 Extra Clear polyethylene sleeves, PPC Industries, Inc., QWheeling, Illin o is. HThree animals per exposure group. --The test article was removed with water. 000099 Table 1 Scoring Criteria for Skin Reactions Reaction Description Score Erythema Edema Barely perceptible (Edges of area not defined Pale red in color and area definable Definite red in color and area well defined. Beet or crimson red in color Barely perceptible (Edges of area not defined) Area definable but not raised more than 1 mm. Area well defined and raised approximately 1 mm. Area raised more than 1 mm. 1 2 3 4 1 2 3 4 Maximum Primary Irritation Score = 8 3. 000100 Animal Number 3B358 3B350 3B353 Table 2 Primary Skin Irritation Test - Albino Rabbits with T-3371 (four hour contact) Irritation Scores for Right Intact Skin Sites After Removal Immediately ER ED 24 Hours ER ED 48 Hours ER ED 2E 4 2 EC 3 2 EN 2 2E 4 2 EC 3 2 EN 2 24 2 EC 3 2 ENX 2 4 Animal Number 3B358 3B350 3B3S3 Irritation Scores for Left Intact Skin Sites After Removal Immediately ER ED 24 Hours ER ED 48 Hours ER ED 2E 4 2 EC 3 2 EN 3 2E 2 4 4 2 EC 2 EC 3 3 2 EN 2 ENX 2 3 Key: C = Chemical burn E = Eschar N * Necrosis X = Epithelial sloughing ED = Edema ER Erythema 000101 Animal Number 3B349 3B384 3B355 Table 3 Primary Skin Irritation Test - Albino Rabbits with T-3371 (one hour contact) Irritation Scores for Right Intact Skin Sites After Removal Immediately ER ED 24 Hours ER ED 48 Hours ER ED 12 2C 3 2 EN 3 11 12 2C 2C 2 2 2 EN 2 EN 2 2 5 Animal Number 3B349 3B384 3B355 Irritation Scores for Left Intact Skin Sites After Removal Immediately ER ED 24 Hours ER ED 48 Hours ER ED 12 11 12 2C 2C 2C 3 2 2 2 EN 2 XE 2 NXE 2 2 2 Key: C = Chemical burn E = Eschar N = Necrosis X = Epithelial sloughing ED = Edema ER = Erythema 000102 Animal Number 3B397 3B395 3B394 Table 4 Primary Skin Irritation Test - Albino Rabbits with T-3371 (three minute contact) Irritation Scores for Right Intact Skin Sites After Removal Immediately ER ED 24 Hours ER ED 48 Hours ER ED 2B 1 2 NOX 2 2 NOX 2 2B 1 2 NO 2 2 NO 2 2B 1 2 NOX 2 2 NOX 2 6. Animal Number 3B397 3B395 3B394 Irritation Scores for Left Intact Skin Sites After Removal Immediately ER ED_______ 24 Hours ER ED 48 Hours ER ED 2B 2B 2B 1 1 1 2 NOX 2 NO 2 NO 2 2 2 2 NOX 2 NO 2 NO 2 2 2 Key: B Blancing X = Epithelial sloughing 0 Eschar N Necrosis ED = Edema ER * Erythema 000103 jg g j. a p p e n d ix I 03P ;^B0J7J Riker Experiment N o .:_____________________ PROTOCOL 7. Acute Primary Skin Irritation Test________ ______________ ____________________________________ SPONSOR: 3M C o irm e rc ia l C h e m ic a ls _______________________________________________________ D ivision CONDUCTED BY: S afety E valuation Laboratory, R iker Laboratories, inc., SL Paul, M innesota TEST A R TIC LE:___ T - -% ?1_________________________________________________________________________________ CONTROL ARTICLE: _________________________________________________________________________________ PROPOSED STARTING/COM PLETION DATE O F TEST: ~ " A 5______________________________________ TEST SYSTEM: Fem ale New Zealand White Albino Rabbits SOURCE: O .'T c P l A j /) A E i , I r L j V F K / PA O B JE C T IV E : To determine the irritation potential of the test article to the skin o f ___ii___animals. Rabbits were selected as the test system due to their historical use, sensitivity to irritants, ease of handling and general availability. METHOD: The animats will be housed in standard wire-mesh cages in temperature and humidity controlled rooms with fo o d i 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. Prior to the application of the test article, the hair will be clipped from the back and flanks of each animal a n d ______2_______ test sites selected lateral to the midline of the back approximately ten centimeters apart___2__ of th e ___2__ sites will be abraded by making four epidermal incisions, two perpendicular to the other two, while the other test site(s) will remain intact. The test article (___Li__________ ) will be applied t o __2____abraded a n d ______ intact site(s) on each animal,-'covered with _______ and secured with ~ - - L'] The trunk of each animal will then be wrapped with impervious plastic sheeting which will occlude the test article during the 1 day exposure periocf O n e hourcaruf^K hoan kfter removal of the test article, the intact and abraded test sites will be examined and scored separately for erythema and edem a on a graded scale of 0 to 4b. The average irritation produced will be evaluated by adding the mean scores for erythema and edema of the intact test sites onfcand 40 hours-post removal-of the test article. Siww- -lariyr-tho m ean scores fo r e rythemo ond odoma of the abradod tost sites -wlll-be-added. These two values will be totaled and divided by-feifc to obtain the mean primary irritation index and then assigned a descriptive primary skin irritation rating as follows: i ^ f i fa Y t i (-> bt-'Tz h "o*r n v .ih ii'j Mean Primary Irritation Score os tc 0 0.1 -0 . 5 0.6-1.5 1.6-3.0 3.1 - 5 .0 5.1 -6 .5 6.6 - 8.0 Descriptive Rating Non-irritating Minimally Irritating Slightly Irritating Mildly Irritating * Moderately Irritating Severely Irritating Extremely Irritating " iV E D J \FEB 211983 TY lVALUA.TIOK' , ) Sponsor The rating for a test article may be increased if the reaction caused is beyond erythem a and edema and are deemed to be of importance in the interpretation of the results. All raw data generated by the study director and the final report will be stored in the Riker Laboratories' Archive, St. Paul, Minnesota. * one si^ht: one hr. application, .?nd sitht 4 hr. application. S. Purina Rabbit Chow, Ralston Purina Co., St. Louis, Missouri b Draize: Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics (1965) Published by the Editorial Committee of the Association of Food and Drug Officials of the United States Read each site upon re.i.ovnl of test substance and 1 and 2 c.'avs. /.o 4 Datei-' Study Director Date Form 1*171-12--PWO 000104 Riker Experiment N o .: 0883EB0079 8. APPENDIX I (concluded) Deviations and/or Amendment to Protocol . In addition to the four hour and one hour contact applications an additional application of three minute contact with three animals w ill be dosed._________ Study Director 3/3/83 Date Due to a delay in report processing the proposed completion date should be amended to 6 /8 3 . - o . ***-*- .&o-i ^ 6 /3 0 /8 3 Study Director Date Study Director Date Study Director Date Study Director Oste 000105 APPENDIX I I Principal participating Personnel Involved in the Study 9. - Name D. M. Markoe, J r ., 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 000106  10. APPENDIX XXI 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. 000107 11. APPENDIX IV Quality Assurance Statement This study is not o ffic ia lly 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 fa c ilit ie s are examined on a three month schedule'. In addition a select number of Research & Development c\ studies are routinely picked at random from the Archives by the Compliance Audit department for review. \ 000108