Document DMwqmQQ5vX0gYmKONoXgkVB6Q

T- 3 ? m % -o m 28 Day Percutaneous Absorption Study with FC-129 in Albino Rabbits // // Experiment No. Conducted At: Dates Conducted: Conducted By: Reviewed By: dc : M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick 0979AB627 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 24, 1979 to December 18, 1979 ) K.o K. D. O'Mailed), BS Advanced Toxicologist Study Director Date sflarari__ K. L. Ebbens,"BS Date Supervisor, Acute Toxicology 000254 Summary ^EST COPY AVAILABLE i A 28 day percutaneous absorption study with FC-129 was conducted from October 24, 1979 to December 18, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rabbits ranging in body weight from 1.75 to 2.42 kg. The test article was administered by dermal application to ten male and ten licmale rabbits at a dosage level of 5,000 mg/kg body weight for a 24 hour exposure period^- Six mortalities were noted which occurred between days two and three. The untoward behavioral reactions which were noted during the 28 day study consisted of lethargy, hypoactivity, prostration and blood was noted the urine. Onset of the reactions occurred from day 1 to day 6 and all reactions subsided by day 7 or death precluded recovery. Body weight losses were noted in two of the animals which survived the observation period. Necropsies of animals which died acutely, generally revealed pale, mottled ' livers and blood in the urine with one animal exhibiting a dark green spot on the brain. Necropsies were also performed on animals which survived the study period and revealed no visible lesions, with the exception of one animal which had an atrophic spleen. Preliminary serum analysis (see Appendix V) indicates dermal absorption of FC-129 in 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*1 was to determine the percutaneous absorption potential of FC-129 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on October 24, 1979 a A preliminary rangefinder study was conducted to determine the appropriate dosage level to be used in this study. b Riker Toxicity Experiment No.: 0979AB0627, Test Method 699 000255 BEST COPY AVAILABLE 2 and completed on December 18, 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. 000256 1 S T COPY AVAILABLE 3. Mo thod Young adult albino rabbits of the New Zealand breed-- were used in this Lost. All animals wore hold under quarantine for several days prior to testing with only animals which ap|Jourod 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 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 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 Pel Freez, Inc., Rogers, AR -- Purina Rabbit Chow, Ralston Purina, St. Louis, MO 000257 BEST COPY AVAILABLE 4. 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, 7, 14 and 20 day body weights were recorded (Table 2) as were 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 are contained in Appendices I - IV. 000258 TAULE 4- BEST COPY AVAILABLE ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-129 Mortality and Body Weight Data a Dose-- (mg/kg) Sex Animal Number Individual Body Weights (kg) Test Day Number 0 14 Number Dead Number Tested Percent Dead 5000 M 9B2593 M 9B2591 F 9B2689 F 9B2646 2.22 2.19 2.07 2.26 1.29 1.44 1.41 2.03 0/4 0 2000 M 9U2594 M 9B2597 F 9U2684 F 9B2687 2.10 2.09 2.17 2.02 1.76 2.00 2.14 1.87 0/4 0 1000 M 9B2574 M 9B2577 F 9B2690 F 9B2693 2.20 2.29 2.37 2.16 2.31 2.37 2.24 2.18 0/4 0 -- Test article was dosed undiluted 000259 TABLE 2 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-129 Mortality and Body Weight Data 6 Dose^Sex (mg/kg) Animal Number Individual Body Weights Test Day Number 0 7 14 Number Dead Percent 28 Numner rested Dead 5000 M 9B3056 2.20 1.82 1.78 M 9B3062 2.40 1.97 2.11 M 9B3057 2-42 2.14 2.43 M 9B3063 2.10 (2 Days) -- M 9B3072 1.75 1.91 2.12 M 9B3077 2.04 2.04 2.05 M 9B3032 2.04 1.59 1.73 M 9B3038 2.38 2.15 2.37 M 9B3033 2.36 2.23 2.23 M 9B3039 2.28 1.98 2.25 2.18 2.41 2.75 -- 2.44 2.30 2.18 2.45 2.60 2.42 1/10 10 5000 F 9B2985 2.23 (3 Days) F 9B2991 2.17 (3 Days) -- F 9B2936 2.23 (2 Days) -- F 9B2942 2.00 1.61 1.56 F 9B2960 2.37 (2 Days) -- F 9B2966 2.07 1.70 2.05 F 9B2955 1.87 1.89 2.15 F 9B2967 2.04 1.81 2.05 F 9B2937 1.98 1.72 2.04 F 9B2943 2.05 (2 Days) "***"" ---- -- -- 1.84 -- 2.43 2.44 2.33 2.32 5/10 50 -- Test article was dosed undiluted Necropsy Necropsies performed on animals which died acutely, generally revealed pale mottled liver and blood in urine , with one animal having a dark green spot on the .brain. Animals which were sacrificed upon termination of the study revealed no visible lesion! with the exception of one animal which had an atrophic spleen. 000260 Dose (mg/kg) 5000 2000 1000 TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-129 Sugary of Reactions Sex Reaction Time of Onset -- Number Affected Following Dose Humber Dosed Administration Cessation of Reaction -- Following Dose Administration M Hypoactivity F No significant reactions M No significant reactions F No significant reactions M No significant reactions F No significant reactions 2/2 Day 9 ------ ---- until termination ---- ---- Time of Death Following Dose BISTGOW 000261 Time when first animal in the dose group exhibited the reaction -- Time when no animal in the dose group exhibited the reaction Dose (mgAg) 5,000 5,000 TABLE 4 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS With FC-129 Summary of Reactions Sex Reaction Tima of Onset Number Affected Followinq Dose Number Dosed Administration Cessation of Reaction Following Dose Administration M Hypoactivity Lethargy Prostration Blood in urine F Hypoactivity Prostration Blood in urine 1/10 2/10 1/10 1/10 4/10 1/10 2/10 Day 6 Day 5 Day 1 Day 1 Day 1 Day 1 Day 1 Day 7 Day 6 Until death Until death Day 3 Until death Until death Time of Death Following Dose Day 2 Day 2 Day 2 Day 2 9 m ^ Time when first animal in the dose group exhibited the reaction -- Time when jno animal in the dose group exhibited the reaction 000262 CD Uiki.T Kxpurimeni: Nu. : APPENDIX I PROTOCOL \ )rtUO>*..j. I 9- TEST: Single Dose 20 Day Percutaneous Absorption Study SPONSOR: 3M 0 o - p - c yr, C 0\pvr<\\c e>S}.______________________________________ _ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: \- C - > Ckc-i__________________W V S t O ________________________________ _ CONTROL ARTICLE: _ JO Vlfi _ ___________________________________________ PROPOSED STAKTINO/COMPLETION DATE OE STUUY~ || -pj / | V p TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: UF Pel Ereex, Inc., Royers, Arkansas Number: IO / iO Weight Range: 3. -%W.cy' objective: The objective of this study will be to determine the percutaneous absorption potential of the test article in albino rabbits. Rabbits were selected as th< test system for their.historical use in dermal absorption studies, ease of handling and general availability. method: The animal:;, 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 bo 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 m g/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 t h '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.1, 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. V O 0 O ' V G v y m ^ i l e - /icw Sponsor " / r /v i Date v n rW lik / ' Study Director A u/i/-,*, Date BEST COPY AVAILABLE 000263 Ki.kujr. Experiment No, APPENDIX I (Continued) PKcmxxn, L M M . 10. 'TEST: A cu te D cpnal T o x ic it y K jjn g e fin k in g tud y SPONSOR: 3M Wf.fh/ U lfr/ltJfJJl/-______ BEST COPY AVAILABLE Divisio CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesot TEST ARTICLE: 'jTQ- j 'J)Cj ______________ CONTROL ARTICLE: .//'/) I'HOPOSED STAl<TINO/X:dMPLETiON DATE OP STUDY: JQ JG ~ T M D . TEST SYSTEM AND SOURCE: New Zealand White AiLrbino Rabbits Sex: Pol-Preoz, Inc., Rogers, Arkansas Number: ,Q Body Weignt Range : 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 S,fCC1, 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-- will1bo fitted on each animal and the trunk wrapped with impervious plastic sheeting which will occlude the test article. The anima) 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 stor 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. Sponsor ' K>Z\ Date Study Dii -r Da 000264 BEST COPY AVAILABLE Riker Experiment APPENDIX I (Concluded) Amendment to Protocol 1. ' \\,^ \ r.^'/v/rV'i- , lo ^ ry j^ y \ a Q rvw ^ i^ La . c S V c JC'loQrvo __ \-,vi\'.v?' 1 <\' - 'V-i. \Uv I >~'V^ . K V l * . fifeOLpy) \sSL* 11 2. \ V `,. tv'V> *\'| Vv VK\I*K. v \ ^ 4 o y ^ Study Director!) Date u ->'0 9, V>o.- cVv/vororQ ^ T f \ n4' 3> \ U . \ rvfyy^g. ^ ~t o vA/v.'v X ' v ^ v H . \ V k'-j w Study Director (j 13hi? Date . j L y w . Q g < 9 __ IO - \i\ ^ \ ( W 4. 'Q ^ _V__._____-_V_-_,______M____V_____C__4_-_U_ (________-_O_V__.___ v V Study Director t j >___ C U A a ^ ji y tL b Q O j v \ c 1 ?[An ft) Date c v ry; o .^ :v iv ^ fA . -l\pJL _.LPk^--LQ c>lni<P *S -J3 / fe v d n ) -\:> i<V) \uYAfY>Wo,^ *Study Director ^,,fc0 13ate Study Director Date 6 Study Director Date 7. Study Director Date 8. Study Director 000265 Dato T COPY AVAILABLE APPENDIX II Principal Participating Personnel Involved in the Study 12 Name K. L. Ebben s , DS Function Supervisor, Acute Toxicology K. D. O'Malley, BS Dr. V. Pol;hap rayada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory 000266 a p p e n d i x III Composition Characteristics 13. 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. 000267 a p p e n d i x IV Quality Assurance Statement 14. 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 sure examined by Laboratory Quality Assurance on a three month schedule. 000268