Document qmMDV0komvQN5p12GQ1ma8LwK

j\R l% S-0J55 28 Day Percutaneous Absorption Study with FC-95 in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: de: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick 0979AB0632 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 25, 1979 to December 17, 1979 *% V - V ' -\j ( I'I'Ll -------- K. D. O'MalieV/ BS Advanced Toxicologist Study Director I if * Date K. L. Ebbens, BS Date Supervisor, Acute Toxicology 003732 1. 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 study^- 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. -- Riker Toxicity Experiment No.: 0979AB0632, Test Method 699 003733 2. Method a Young adult albino rabbits of the New Zealand breed-- were used in this tost. All animals were held 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. The rabbits were housed individ ually in stainless steel, wire-bottomed cages and maintained on a standard b laboratory ration-- with food and water available ad libitum. An initial rangefinding study was conducted using two male and two female rabbits for each dosage level. The trunk of each animal was clipped free of hair and the test article placed on the surface of the intact skin which covered approximately 4Q'i 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 dermal 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 admin istration) 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 percutaneous 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 g- Pel Frecz, Inc., Rogers, AR -- Purina Rabbit Chow, Ralston Purina, St. Louis, MO 003734 3. period the tost article was removed from the dermal surface of the animals and the animals returned to their cages for the following 28 days. Initial, 7, 1.4 and 'Ml day body weights were recorded (Table 2) as wore any pharmacotoxic 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). The protocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement arc contained in Appendices I - IV. 003735 TABLE 1 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-95 Mortality and Body Weight Data 4 Dose^(mg/kg) Sex Animal Number Individual Body Weights (kg) Test Day Number 0 14 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. 003736 TABLE 2 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-95 Mortality and Body Weight Data 5. Dose^ _Opy Animal (mg/kg) Number Individual Body Weights (kg) _______Test Day Number__________ 0 7 14 28 Number Dead Percent Number Tested Dead 5000 M 9B3040 2.10 M 9B3046 2.21 M 9B3052 1.90 M 9B3058 2.30 M 9B3042 2.16 M 9B3048 2.18 M 9B3054 2.27 M 9B3060 2.06 M 9B3044 2.28 M 9B3050 2.25 1.99 1.67 1.61 1.88 1.81 1.84 2.12 2.00 2.15 1.97 2.02 1.85 1.84 2.15 1.92 2.08 2.30 2.23 2.36 2.04 2.46 2.15 2.20 2.33 2.24 2.47 2.52 2.33 2.64 2.34 0/10 0 5000 F 9B2944 2.07 F 9B2950 2.13 F 9B2956 2.12 F 9B2962 2.09 F 9B2946 2.15 F 9B2952 1.93 F 9B2958 2.10 F 9B2739 2.37 F 9B2948 2.14 F 9B2954 1.82 1.86 2.01 1.85 1.99 2.06 1.88 1.94 2.24 2.05 1.75 2.14 2.07 2.04 2.20 2.36 1.97 2.17 2.34 2.21 1.99 2.45 2.32 2.38 2.54 2.79 2.29 2.40 2.47 2.41 2.32 0/10 0 -- The test article was dosed as a suspension in water Necropsy Necropsies performed upon termination of the study revealed no visible lesions. 003737 Dose (mg/kg) TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-95 Summary of Reactions Sex Reaction Time of Onset Humber Affected Following Dose Humber Dosed Administration Cessation of Reaction Following Dose Administration 5,000 1,000 M No significant reactions F No significant reactions M No significant reactions F No significant reactions -- -- -- -- -- -- Time of Death Following Dose -- -- -- t 003738 cn Riker Experiment No. : APPENDIX I PROTOCOL Q Q b 3d- 8. ST: Single Dose 28 Day Percutaneous Absorption Study PONSOR: 3M ci &_Q $v>m\PnC ) __________________________________ _ Division INDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota 2ST ARTICLE: Ir- Q, \ja\ feUVg_____________________________________________ _ 2NTR0L ARTICLE: / ft__________________________________________________ ________________ OPOSED STARTING/COMPLETION DATE OF STUDY: n-Tq / >- STt>_________________________ 2ST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: k* 4.,t Pel Freez, Inc., Rogers, Arkansas Number: to* Jo Weight Range: 3-3 r 3JECTIVE: The objective of this study will be to determine the percutaneous absorption potential of the test article in albino rabbits. Rabbits were selected as the test system for their historical use in dermal absorption studies, ease of handling and general availability. 2T1I0D: 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 con trolled rooms with food-- 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 fi.OOO mg/kg to intact skin coverinq approximately 10% total body surface area. A flexible plastic collar^ 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 initiation of 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 findings will 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. Initia.l, 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 responsibility of the sponsor, and the final report will be stored in the Riker Laboratory's 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* o C { Y /OCU) { 3onsor Date Study Director 0 003739 Riker Experiment No. APPENDIX' I (Concluded) PROTOCOL TEST: Acute Dermal Toxici,ty 3anqefin4ix*g Study SPONSOR: 3M J2u i m u ai:2. W X C G . . ___________________________________Division CONDUCTED BY: Safety Evaluation Laboratory, Hiker Laboratories, Inc., St. Paul, Minnesota rr- Q fTEST ARTICLE: ___________________________ __________________________________ CONTROL ARTICLE: JJ!/)_____________________ PROPOSED STARTING/COMPLETION DATE OF STUDY; / / / - / / / / ] TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: Pel-Freez, Inc., Rogers, Arkansas Numbe* : ,, ->, Body Weight Range: ,y - , ffj OBJECTIVE: The objective of this study will be to approximate the acute dermal toxicity of the test article in albino rabbits. Rabbits were selected as the test system for their sensitivity of response, historical data, ease of handling and general availability. METHOD: 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 food-- 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 placed on the surface of the intact skin at single dosages of .Q,(Y Y ) , /,(C) mg/kg, however, if these dosage levels do not adequately characterize''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 sponsor. After administration of the test article, a flexible plastic collar^ 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 posure period (immediately post dose 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 (LD50) 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. a -- Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri -- The collar will be worn for the duration of the study to reduce oral in gestion of residual test article. 003740 Dose (mg/kg) 5,000 TABLE 4 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-95 Summary of Reactions Time of Onset -- Number Affected Following Dose Sex Reaction______ Number Dosed ' Administration M Hyperactivity 5/10 F No significant reaction noted Day 6 -- Cessation of Reaction- Following Dose Time of Death Administration________ Following Dose Day 7 -- Time when first animal in the dose group exhibited the reaction -- Time when no animal in the dose group exhibited the reaction 003741 Riker Experinent No. APPENDIX I (Concluded). A n d n t to Protocol 10. d d /( J--zb1. Qo^- -Vo C. p __ b ifid i---^Ar~Y>/<LS - .L *L 0__ *-o> __>u_ (v ii...Wo ---3/hi J Co*^/>Z 6. 2-.~X^<= tr>M n o o A. Ik ^ ^ ^ Y lQ K / Study Directotr 4 Pr?ifiihcuv\tiI ru'iV i <fav: k L i'hhac C o i ) + Q JL.0 ( o ) ,M ~ ' DaDate 6&. r L ^y SSttuudy Director Date 3` Ql>C..A^ ~V-bs--- z L ^ li--- ^L__ .S-/o3M>-j __-U v* j. 'Q^-i/,0 t 7 0 4 . , ltJ Q AlS k -- UI !1-- <Os4 be__ rs<o 4tw- r/>.vya^fn,Jor> H D dvr\<-Miy I%^/n? Study Directoxr Date __ r..ftirAy:___I k V K A ^iQvla.^___ =t___ .ft ~ **>-Q < 3 __________________________________ 160 ftnQJ & y SSttuudy Director I0/jb'/tf Da te 5 -- CLAL. ~\t' t fo/foWJ>I / 1^ & -r r*\ib b ___-/c. cfnr-p U-^q L- t | >t- Q> l a i t~i*C * i 00 K OdVOoJLiU, Study Directo*r0 TS^M. Date 6. Study Director Date 7. . Study Director Date 8 Study Director Date 003742 APPENDIX II Principal Participating Personnel Involved in the Study 11- Name K. L. Ebbens, BS Function Supervisor, Acute Toxicology K. D. O'Malley, BS Dr. V. Pothapragada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory 003743 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. 003744 a p p e n d i x IV Quality Assurance Statement This study is not regulated by the Good Laboratory Practice Regulation 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. 003745 iiiu.'iiirfiuunespOHuence ce : D. . R i c k e r - 5 3 - 4 re : I-. U. G r i f f i t h - 2 2 D - 2 E !\ A. U b e l - 2 2 U - 2 E APPENDIX V T" K. L. EBBENS - RIKEK SAFETY EVALUATION LAB - 203-1 hul" W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E ubjec' s k in ABSORPTION STUDIES ON FC-143, FC-95, FC-99, FC-134, FC-13S FC-128, FC-129 and FC-98 to*" JUNE 27, 1980 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 fluorochemical 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 C-03746 Internal CoMirsjKKitJeiM.; .!< j. > i m i h . - 7VM-J,-> K. A. Prokop - ZJG-211 !.. U. Winter - 236-2U 15. APPENDIX V (Concluded) COMMERCIAL CHEMICALS DI V IS I ON ANALYTICAL LAB REPORT tfl46 lo W. C. MCCORMICK - 220-2K-02 From V. POTHAPRACADA AND V. BUNNELLE - 236-3A Subiect RIKER SKIN ABSORPTION STUDY Dte June 9 1980 Reference: Commercial Chemicals Division Analytical Request 115669 aFor lack of time only selected set of serum samples was analysed. TOTAL F. PPTM___ Compound Females Pay 1 Day 26 Males Day 1 Day 28 FC-129 26.1 69.6 11. A 23.3 FC-13A 0.2 18.1 18.8 23.y FC-128 A.A 16.5 1.6 10.5 FC-98 FC-135 226. A 6.9 93.1 20.8 271.9 2.3 9A.3 7.6 FC-95 0.9 128.0 10.3 130.2 FC-99 A2.5 53.1 111.5 119.8 129.1 72.7 73.5 66.6 FC-J.A3 Pay_Z. . 10.1 Females Pay-1A 12 .1 Day 28 3.5 Day 7 5 .A Males Day 1A 6 .8 Day 28 A. 6 Mol lio<l of Ann IytiIu : Oxy>*en llowh/CC Tit.IiiiI (.Ion Uollnlc ami D. F. Hagen Anal. Blochem; 87, 5A5, 1978). wx. 'ri/ri^A,_ V. A. Bunnelle VAB/hc ' JC ^ fr^ V. Pothapragad Read and Reviewed by I)y WInLer .ch 003747