Document gaLZJgq4BOEvZrQVrNq2moXVG

28 Day Percutaneous Absorption Study with FC-95 in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted BY: Reviewed BY: dc: M. T. Case K. L. Ebbens P. D. Griffith W. C. McCormick 0979ABO632 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 25, 1979 to December 17, 1979 1 K. D. 0 'Malle-Y, BS Advanced Toxicologist Study Director Date K. L. Ebbens, BS Date Supervisor, Acute Toxicology Summary A 28 day percutaneous absorption study with FC-95 was conducted from October 25, 1979 to December 17, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rabbits ranging in body weight from 1.82 to 2.37 kg. (A preliminary rangefinder study was conducted to determine the dosage level to be used in the study) The test article was administered by dermal application to ten male and ten female rabbits each at a dosage level of 5,000 mg/kg body weight for a 24 hour exposure period. No mortalities were noted during the 28 day study. The untoward behavioral reaction which was noted during the 28 day study consisted of hyperactivity from day 6 to day 7. Body weight loss was noted in one male at the end of the study. Necropsies were performed on all animals upon termination of the study with no visible lesions noted. Preliminary serum analysis (see Appendix V), indicates dermal absorption of FC-95 of albino rabbits, however, due to the limited number of samples analyzed by the sponsor, no concrete conclusion may be drawn. Introduction The objective of this studya was to determine the percutaneous absorption potential of FC-95 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, In., St. Paul, Minnesota on October 25, 1979 and completed on December 17, 1979, was not conducted to support a government submission or marketing permit and is, therefore, not regulated by the Good Laboratory Practice Regulation of 1978. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives. 2@Riker Toxicit:y Experiment No.: 0979ABO632, Test Method 699 2. Method Young adult albino rabbits of the New Zealand breadl were used in this test. All animals were hold under quarantine for several days prior to testing with only animals which appeared to be in good health and suitable as test animals at the initiation of the study used. 2he rabbits were housed individually in stainless steel, wire-bottomed cages and maintained on a standard laboratory ration!i with food and water available ad libitum. An initial rangefinding study was conducted using two male and two female rabbit-- for cacti doijagc IL-vf--l.'.rtitcrunk of each animal was cligi.)cdfree of hair and the test article placed on the surface of the intact skin which covered approximately 40% total body surface area. After administration of the test article, a flexible plastic collar was fitted on each animal;and the trunk wrapped with impervious plastic sheeting which will occlude the test article. The animals were returned to their cages for a 24 hour period after which time the test article was removed from the do-mal surface of the animals. The animals were observed for pharmacotoxic reactions both during the exposure period (immediately post dose administration, one and two hours) and after removal of the test article (daily for 14 days following dose administration) with all reactions recorded (Table 3). Initial and final body weights were also recorded (Table 1). The information derived from the initial rangefinder was used in determining the dosage level for the 28 day peroutaneous study. Preparation of 10 male and 10 female animals for dosing and application of the test article were conducted in the same manner as the rangefinder study with the exception of the collection of blood samples from the orbital sinus plexus prior to application and again on days 1, 7, 14 and 28 after initiation of the study for serum which was frozen for sponsor analysis. After the 24 hour exposure 2@Pel Freez, Inc., Rogers, AR b Purina Rabbit Chow, Ralston Purina, St. Louis, MO period the test article was removed from the dermal surface of the animals and the animals returned to their cages for the following 28 days. Initial, 1.4ari(i28 dziyb(.)dywCiyliLs we--rcr(--carded(Table 2) as were any L.)tiiAriftac(jtoxic signs noted during the 28 day observation period (Table 4). A gross necropsy was conducted on all animals sacrificed on day 28 and all findings recorded (Table 2). 'rhoprotocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement are contained in Appendices I IV. TABLE 1 4. ACUTE DERMAL RANGEFINDER TOXICITY STUDY with FC-95 - ALBINO RABBITS Mortality and Body Weight Data a Dose (mg/kg) sex Animal Number Individual Body Weights Test Day Number 0 14 (kg) Number Dead Number Tested Percent Dead 5000 m 9B2600 m 9B2603 F 9B2636 F 9B2639 2.05 2.42 2.00 2.13 2.28 2.50 2.08 2.10 0/4 0 1000 m 9B2606 m 9B2609 F 9B2642 F 9B2645 2.09 2.14 2.10 2.06 2.30 2.29 2.11 2.23 0/4 0 Test article was administered as a suspension in water. TABLE 2 5. ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY ALBINO RABBITS with FC-95 Mortality and Body Weight Data Dose a Sex (mg/kg) Animal Number Individual Body Weights Test Day Number T- 7 14 (kg) 28 Number Dead Number Tested Percent Dead 5000 m 9B3040 2.10 1.99 2.02 2.46 0/10 0 m 9B3046 2.21 1.67 1.85 2.15 m 9B3052 1.90 1.61 1.84 2.20 m 9B3058 2.30 1.88 2.15 2.33 m 9B3042 2.16 1.81 1.92 2.24 m 9B3048 2.18 1.84 2.08 2.47 m 9B3054 2.27 2.12 2.30 2.52 m 9B3060 2.06 2.00 2.23 2.33 m 9B3044 2.28 2.15 2.36 2.64 m 9B3050 2.25 1.97 2.04 2.34 5000 F 9B2944 2.07 1.86 2.14 2.45 0/10 0 F 9B2950 2.13 2.01 2.07 2.32 F 9B2956 2.12 1.85 2.04 2.38 F 9B2962 2.09 1.99 2.20 2.54 F 9B2946 2.15 2.06 2.36 2.79 F 9B2952 1.93 1.88 1.97 2.29 F 9B2958 2.10 1.94 2.17 2.40 F 9B2739 F 9B2948 F 9B2954 2.37 2.14 1.82 2.24 2.05 1.75 2.34 2.21 1.99 2.47 2.41 2.32 The test article was dosed as a suspension in water Necropsy Necropsies performed upon termination of the study revealed no visible lesions. TABI.E 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY ALBINO RABBITS with FC-95 Surrmary of Reactions Dose (mg/kg) Sex Peacti-on Hur,!>erAffected tilz-,berDosed Time of Onset Following Dose Adrunistration Cessation of Peaction Follo,4ing Dose Actlinistration 5,000 m No significant reactions F No significant reactions ----- --- 1,000 m No significant reactions F No significant reactions --- --- APPENDIX PROTOCOL Riker Experiment I No.: c)q,7qiir-3063,'@ .,c@T: Single Dose 28 Day Percutaneous ?ONSOR: 3m Absorption Study Division )NDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota :'STARTICLE: )NTROL ARTICLE: C-- Q rz m If@ Lo@ 6%A@o IOPOSL:'D STARTING/COMPLETION DATE OF STUDY: :'STSYSTEM AND SOURCE: New Zealand White Albino Rabbits Pel Freez, Inc., Rogers, Arkansas Sex: kA.&Ir Number: too-)o Weight Range: 2--1 3JECTIVE: :,TllOD: The objectiveof this study will be to determine the percutaneous absorption potentialof the test article in albino rabbits. RabbitsWere selectedas the test system for their historicaluse in dermal absorptionstudies, ease of handling and general availability. The animals, selected from a larger colony by health and body weight, will be randomly housed in standard wire-mesh cages in temperature and humidity controlled rooms with foods 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 trunk of each animal will be clipped free of hair and the test article applied as a single dosage of _tLg@00 mgag to intact skin coverinq approximatelylp% total body surface area. A flexible plastic collarb will be fitted on each animal and the trunk wrapped with impervious plastic sheeting, which will occlude the test article. _The animals will then be returned to their cages for a 24 hour exposure period after which the test article will be removed. Prior to the'application,blood samples will be collected from the orbital sinus plexus and again on days 1, 7, 14, and 28 after initiationof the study for serum which will be frozen for sponsor analysis. A gross necropsy will be conducted on all animals which may die during the conduct of the study as well as all animals sacrificed on day 28. All gross findingswill be recorded and tissue samples of liver, spleen, brain, kidney and bone marrow (sternum)will be fixed in 10% buffered formalin for possible future microscopic examination. initial, 7, 14, and 28 day body weights will be recorded as well as any pharmacotoxic signs noted during the conduct of the study. All raw data, other than the blood analysis data which will be the responsibilityof the sponsor,and the final report will be stored in the Riker Laboratory's Archives-,St. Paul, Minnesota. a Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri The collar will be worn for the duration of the study to reduce oral ingestionof residualtest article. :)onsorme cc,,V" Date Study Dirictor6 Date Riker i@xperiment No.: APPENDII I (Concluded) PR(OTOCOL . TEST: Acute DgTmal Toxic] @ty n fin4itaI St-idy SPONSOR: 3M p CONDUCTED BY; Safety Evaluation Laboratory, Riker TEST ARTICLE: CONTROL ARTICLE: PROPOSED START ING/COMPLrT TEST SYSTEM AND SOURCE: ION DATE OF ST DY: New Zealand White Albino Pel-Freez, Inc., Rogers, La 1>oratories, Inc., St Paul, Rabbi@Cs Arkansa-9 Sex: c Number: weig t Range: 9. Division Minnesota OBJECTIVE: METHOD: The objective of this study will be to approximate the acute dermal toxicity of the test article in albino rabbits. Rabbits were solucted as the tcst system for their sensitivity of response, historical data, ease of handling and general availability. The animals, selected from a larger colony by health and weight, will be randomly housed in standard wire-mesh cages in temperature and humidity controlled rooms with foo*dland 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 trunk of each animal will be clipped free of hair and the-tes article placed on the surfar-aof the intact skin at single dosages not adeq mg/kg, however, if these dosage levels do te y charact;@ize the toxicity of the test article, additional animals will be administered the test article at supplemental dosage levels. Any additional dosage levels will be documented and filed with this protocol. The test article will be administered to the animals in the form received from the spons r. After admini@ptrationof the test article, a flexible plastic collar-B will@be fitted on each animal and the trunk wrapped with impervious plastic-sheeting which will occlude the test article. The animals will be returned to their cages for a 24 hour exposure period after which time the test article will be removed from the dermal surface of the animals. The animals will be observed for pharmacotoxic reactions both during the ex- liosure period (immediately 1)ostdose administration, one and two hours) and after removal of the test article (daily for 14 days following dose adminis- tration) with all reactions being recorded. Initial and final body weights will also be recorded. The acute median lethal dose (LDSO) of the test article will be approximated. All raw data and the final report will be store( in the Riker Laboratories Archives, St. Paul, Minnesota. Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri The collar will be worn for the duration of the study to reduce oral ingestion of residual test article. spon-sdr Date t"y Diiec Dat ty Dose (mg/kg) 5,000 TABLE 4 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-95 Summary of Reactions Sex PRacti-on Time of onset atiurber Affected Following Dose tlu:7tbeDrosed ' AeLrunistration m Hyperactivity 5/10 F No significant reaction noted Day 6 Cessation of Peaction@l Following Dose Ae-ninistration Day 7 a Time when first animal in the dose group exhibited the reaction Time when no animal in the dose group exhibited the reaction C4 2. V"L 3. 4 n 4. 4,e 5. 6. 7. Rtkor Experiment.No.: APPENDIX I (Concluded).. Amndment to Prot7ocol 10. 4c, i Study Directcik (09 Date Study Directibr 4@,J 1 A@e,4 6 4A@,-c,,,:, nm-- 4"- Date Study Directoe %j Date Study Diredtor .2Q= d@el '-bate -7'oFTr;ii i(o&fy)cj-kk,,,,, study Director(i Date -T- Study Director Date Study Director Date S. Study Director Date APPENDIX Il Principal Participating Personnel involved in the Study Name K. L. Ebbens, BS K. D. O'Malley, BS Dr. V. Pothapragada G. C. Pecore Function Supervisor, Acute Toxicology Advanced Toxicologist Study Director Co=nercial Chemicals Chemist Supervisor Animal Laboratory 12. APPENDIX III Composition Characteristics This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. 13. APPENDIX IV Quality Assurance Statement This study is not regulated by the Good Laboratory Practice Regul;tion of 1978 and therefore a statement signed and prepared by the Quality Assurance group is not applicable. This study was, however, audited by the Quality Assurance group. In addition to the data audit, different significant phases for studies underway in the Toxicology Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule. iffit!#Iido t-Ln febpui buel bLe It.Ricker - 53--l 14. 1). (;riffith - 220-2h A. Ubel - 22U-21-. APPENDIX V L. EBBENS - RIKER SAFETY EVALUATION LAB 203-1 W. C. MCCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES 220-2E SKIN ABSORPTION FC-128, FC-129 JUNE 27, 1980 STUDIES ON and FC-98 FC-143, FC-95, FC-99, FC-134, FC-135, Please consider this an authorization for your laboratory to release the dermal toxicity/skin absorption studies conducted on the above mentioned compounds. It is understood that the studies are being issued in an incomplete form insofar as the fluorochomical analysis of the serum samples have not been completed and will not be included in the report. Preliminary serum sample analysis indicates absorption of the compounds. The serum data analysis are not sufficient enough to draw any concrete conclusions concerning comparitive toxicity. However, the animal data you have generated addresses this matter in a broader context. It is not certain when the remaining samples will be analyzed and their completion should not hold up your report any longer. Thank you for your patience in this matter. WCM:klh it.A. 1'rijitt)i)Z.'S(j-Zlt i). Witater APPENDIX V (Concluded) COMMERCIAL ANALYTICAL CHEMICikLS DIVISION LAB REPORT #146 Iii W. MC(X)RMI(:K 220-2@.-02 Ficirn V. POTHAPRAGADA AND V. BUNNELLE - 236-3A SLoect RIKER SKIN ABSORPTION STUDY Gulf.. June 9, 1980 v@V a 9;f>t Reference: Commercial 015669 Che"cals Division Analytical Request For lack of time, only a selected set of serum samples was analyzed. T(YRAL F. ppm Compound FC-129 FC-134 FC-128 FC-98 FC-135 FC-95 FC-99 Females Day 1 Day 28 26.1 69.6 0.2 18.1 4.4 16.5 226.4 93.1 6.9 20.8 0.9 128.0 42.5 53.1 111.5 119.8 Males Day 1 Day 28 11.4 23.3 18.8 1.6 23.9 J.U.!) 271.9 94.3 2.3 7.6 10.3 130.2 129.1 72.7 73.5 66.6 I)ay7 Females L&X 14 Day 28 l@ay 7 Males pay. k4 1).*i2y8 3 LO.i 12.1 3.5 5.4 ().d /,.(j ()xy)-4kii-i (.14)l1t14.lltiit. D. F. liagenA,nal.Biochem;8-/,545,1918). V. A. Bunnelle VAB/hc fl.A V. Pothapragada Read ar-d Reviewed by