Document MMM53XjJGQ951geQxLxrz5bvL

28 Dermal Percutaneous Absorption Study with FC-128 in Albino Rabbits Experimnt No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick 0979ABOG29 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 25, 1979 to December 17, 1979 4c) Y,. D. 0'14alld, BS Advanced Toxicologist Study Director Date X. L. Ebbens, BS Date Supervisor, Acute Toxicology Summary A 28 day percutaneous absorption study with FC-128 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 1.95 to 2.90 kg. The test article was administered by dermal application to ten male and ten female rabbits a dosage level of 2,000 mcrag body weight for a 24 hour exposure period. No mortalities or untoward behavorial reactions were noted during the 28 day study. Body weight losses were noted in three females 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 AppendixM) indicates dermal absorption of FC-128 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.L3was to determine the percutaneous absorption potential of FC-128 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., St. Paul,iMinnesota 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. 1 2@A preliminary rangefinder study was conducted to determine the appropriate dosage level to be used in this study. b Riker Toxicity Experiment No.: 05.79ABO629, Test Method 699 2. Method Young adult albino rabbits of the New Zealand breea were used in this All. aiiiincalw:c;r(-,held uncA4Lrquarantinl, for several days prior to testin(j w.LL]ionly aniiiial.w-k;iielial.)iy-,arteod be in good health and suitable as test anittialsat the iriiLiaLion of the study used. 'Xhe rabbits were housed individually in stainless steel, wire-bottomed cages and maintained on a standard laboratory rationl' 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 trurxkof each animal was clipped free of hair and the test article placed on the surface of the intact skin which covl,red approximately 40% total body surface area. After administration of the test article, a flexible plastic collar was fitted on each animal k-md 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 de-ml 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 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 a Pel Freez, Inc., Rogers, AR Purina Rabbit Chow, Ralston Purina, St. Louis, Mo 3. 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 28 day body welcititswar(:-recorded (Table 2) as were any phaxmacotoxic signs noted during the 28 day observation period (Table 4). A gross necrojisy 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. 4. ACUTE DELTMAL LiANGEr-INDER TOXICITY STUDY - ALBINO with FC-128 Mortalityand Body Weight Data RABBITS a Dose Sex (mg/kg) Animal Number Individual Body Weights Test Day Number 0 14 (kg) Number Dead Number Tested Percent Dead 5000 2000 1000 m 9B2582 m 9B2585 F 9B2629 F 9B2632 m 9B2598 m 9B2601 F 9B2648 L., 9B2627 m 9B2604 m 9B2607 I., 9B263U F 9B2633 2.16 2.34 2.07 2.00 1.18 1.96 1.95 1.94 2.30 2.26 1.98 2.34 2.25 (3 days) 1.97 2.13 2.32 2.41 2.03 2.20 2.19 2.57 1.87 1.99 0/4 0 1/4 25 0/4 0 Test article was dosed as a suspension in water 5. TAIJLI-. 2 ACUTE IILI<CU.VANLUUASJ3SOW.V]:UN'IIOXICI'RSYTUDY - ALBINO RABBITS with FC-128 mortality and Body Weight Data Dose a (mg/kg) Sex Animal Number Individual Body Weights (kg) Test Day Number 0 7 14 28 Number Dead Number Tested Percent Dead 2000 m 9B3001 2.52 2.35 2.57 2.88 0/10 0 m 9133007 2.35 2.43 2.66 2.96 m 9B3013 2,59 2.26 2.52 2.84 9B3003 2.50 2.04 2.39 2.77 9B3009 2.09 2.15 2.26 2.51 9B3015 2.31 2.37 2.59 2.87 9B3005 2.13 1.85 2.10 2.46 9B3011 2.04 1.71 1.87 2.50 m 9B3074 2.07 1.98 2.29 2.49 m 9B3078 2.06 2.18 2.43 2.75 2000 F 9B2969 1.95 1.79 2.05 2.48 0/10 0 E., 'JI321)75 2.13 2.18 2.40 2.67 F 9B2981 2.21 2.24 2.54 2.82 I., 9B2987 2.34 2.33 2.44 2.70 r ')B2971 -42.41 1.87 2.05 2.37 F 9B2977 2.13 1.91 2.25 2.35 F 9B2983 1.94 2.13 2.37 F 9B2989 2.21 1.97 2.12 2.36 F 9B2973 2.19 2.14 2.37 2.50 F 9B2979 @-,@2.38 1.73 1.57 1.79 2@Test article was dosed as a suspension in water Necropsy Necropsies performed upon termination of the study revealed no visible lesions Dose (mg/kg) 5,000 2,000 1,000 TABLE 3 ACUTE DEPI-IAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS Sex R.-@acti-on with FC-128 StL-i.-.iaor-yF R-3ac%';-O'IS t]tLt:%IA>fefrected Ilt!:7beDrosed Tirteof onsec Polla,4ing Dose A6--unistratieN.1 Cessa'6i-on o;- Rea:t;lz).-I Follow;-ng Dose %@Lnin--s . m Hypoactivity 1/2 Lethargy 1/2 F No significant reaction Day 9 Day 14 --- Day 14 Until-termination --- m No significant reaction F No significant reaction m No significant reaction F No significant reaction --- ----- ------- la Time when first animal in the dose group exhibited the reaction Time when no animal in the dose group exhibited the reaction TABLF, 4 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-128 S"lr:naryof- Raacu;-Ols Cessation @f Reaction o-f-Ons-et-- rollo-.@;ng Dose T; Dose (m /k Sex Reeac-ti-on tiLLm!@,ar-Affec%-edF.ollawing Dose tit!;7..berDosed AA-,Unistration A&nin;-;tration 2,000 m No significant reaction p No significant reaction --- i(ikvr FXljurillivAiNLu. APPFNDIX I Lil(LYI-(jcuj, Single Dosc 28 Day PercutanoouS Absorption Study SPONSOR: 3M !2 CONDUCTED BY: Safety Evaluation Laborator@, Riker Laboratories, Inc., St. Paul, TEST ARTICLE: CONTIZOL ARTICLE: IJA*I'LU-i;-' STUDY: SYS'1'1-'AM141) SOUI@CE: Now '/,caland White Albino Rabbits Sax: 13ul l-'rL@ez,Inc., Rogers, Arkansas Number: io 4-1o Weight Range: Division Minnesota kq OLIJI-C'rIV L: IrliL-objective of this study will be to determine the parcutaneous absorption lx>telltiiiolf Llit.t-c.-;tarticle in albino rabbits. Rabbits ware selected as the Lest system for their historical use in dermal absorption studies, ease of handling and general availability. aiii.iitztl:@, froin iA 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@l and water offered ad libitum. Each animal will be assigned a numbered car tag, which will correspond to a card affixed to the outside of the caye. The trunk of each animal will be clipped free of hair and the test article applied as a single dosage of a,..2ot,)mg/kg to intact skin coverinq approximately 10% total body surface area. A flexible plastic b collar will be fitted on each animal and the trunk wrapped with impervious i.31asticsheatinq, 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 wili 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 dia durizi(jtiil-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. Initj,.a.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. a 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. Sponsor Date Study Di@recEor Dite Iiikur ExijuriiiienLNo. Alli'l-.NI)IIX ,/--tIl9. TEST: Acuti-- Dlril-l roxiciLy Hangufi rsg SPONSOR: 3M CONDUCTEI) BY: Safety E;,@,I?a tinn Laboratory, TEST ARTICLE: Riker Laboratories, Division Inc., St. Paul, Minnesota I'li@C)I>'ODSLS'rA 14'I'NlG/CO SY@;*]'I-:AMN[) MI>LL'I'IC)NL)AI1'1:u.l-' S'I'UUY: N(.-wZt.-.AlaiiWdliitc AJI.)ln6 Rabbits tlul-Frcuz, Inc., Rogers, Arkansa4 Sax: Numbe Body Weig t Range:'-.-@@.-'J@A@-Z' z OBJECTIVE: The objective of this study will be to apl3roximate the acute dormal toxicity of the test article in albino ral)L)itsR.abbitswarc selectedas the test system for their sensitivity of response, historical data, ease of handling and general availability. MI-I"I'IIOD: The ;Aniiii;AlL;s,uiceled from a larger colony by health and weight, will be randomly housed in standard wire-mesh cages in temperature and humidity controlled rooinswith fo6dE 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 p@aced on the surface of the intact skin at single do.,;ay4-.o!i;c ,.,2lYr],L (J(r)mg/kg, however, if theso dosage levels do not adequat7c.1ycharei'cterize"tthoexicity of the test article, additional animals will be administered the test article at supplemental dosage levels. Any 4dditional dosage levels will be documented and filed with this protgcol. The test article will be administered to the animals in the form received from the sl)onssr. After admini*tration of the test article, a flexible 1.)lasticollar- will@be 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- posurc 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 @ethal dose (LD50) of the test article,will be approximated. All raw data and the final report will be sto: 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. Sponsor Date Study Dikect& D 3. 7- 4. 5. 6. 7. 8. Riker Experimat No..- APPENDIX I (Concluded) Amendment to Protocol 10. ?W(x 001 Study DLre;ctor Date 0/1 Stu6y ]Dirac#or-- IAA NkdiA" 4@.k, ir\A(*iAAAAOA Study Di've ig: Date J4 Study Director Date study Director Dat Study Director Date Study Director Date Stu4y Director Date APPENDIX II Principal Participating Personnel Involved in the Study Name K. L. Ebbens, BS K. D. O'Malley, BS Dr. V. L'oLhal3racjada .G. C. Pecore Function supervisor, Acute Toxicology Advanced Toxicoligist Study Director Commercial Chemicals Chemist Supervisor Animal Lak>oratory APPENDIX 111 12. 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 ouality 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 groul) 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. ItIIt -II I.iI( of It-.,1)4)1141( -1 lf.i- li.(;riffitli 220-2@. 1:.A. Ubal - 220-2L- APPENDIX V 14. ..K. I.. EBBENS - ItIKE-11SAI'-L-TYL-VALUATION LAB 203-1 W. C. McCORMICK - ML-*L)ICAL)EPT. - IROXICOLOGY SERVICES - 220-2E SKIN ABSORPTION S'IUDLI'-O.NS FC-143, I:C-128, FC-129 and FC-98 JUNL-'27, 1980 FC-95, FC-99, FC-134, FC-135, 3M lllease consider this an authorization for your laboratory to release Lito dermil toxicity/skin absorl)tioit studies conducted on the above iiientionodcompounds. It is understood that the studies are being issued in an incomplete fonn insofar as the fluorochemical analysis of the serum samples li.ivneot been completed and will not be included in the report. I'veliminary scruittsainpleanalysis indicates absorption of the cotnl)otinds.The serum data analysis are not sufficient enough to draw any concrete conclusions concernin& comparitive toxicity. itowever, titeanimal data you have generated addre.-isesthis matter in a I)roader colitext. It is not certain when the remaining samples will be analyzo.%d ;tiidtlicircompletion sliouldnot hold up your report any longer. '1*)iziynoku for your paticticein this matter. -A-4 WCM:klh 14 -Is 1.61 ( I$# I I* '.I b4 Ada% to-$ 44 1 1(.A. I*i*ijit)i2j*.16-21$ li. Witater Z36-20 APPENDIV V (Concluded) COMMERCIAL ANALYTICAL CHEMICALS DIVISION IAB REPORT #146 1(.# W. C. MCCOITMICK - 220-2E-02 Frorri V. P(YRIIAPRAGAI)A AND V. BUNNELLE 236-3A V,Y RIKER SKIN ABSOIU'TION STUDY ujl(.. June 9, 1980 Reference: Commercial Chemicals Division Analytical Request 015669 For lack of time, only a selected out of serum samples was analyzed. Compound FC-129 FC-134 FC-128 FC-98 FC-135 FC-95 FC-99 T(YRAL F, ppm Females Day 1 Day 28 Males DeX 1 DaZ 28 26.1 69.6 11.4 23.3 0.2 18.1 18.8 23.9 4.4 16.5 1.6 10.5 226.4 93.1 271.9 1)4.3 6.9 20.8 0.9 128.0 2.3 10.3 7.6 130.2 42.5 5.3.1 Ul. 5 3.19.8 129.1 72.7 73.5 66.6 Day 7 L-'entales Day 14 D2X 28 L)!!X_7 Mali--s Ray 14 1).iy@8 iec- j.4 10.1 12.1 Me-Ilifiotlof Asi:iI@/iis#a: tlxyj-.iL-iTi 0. F. Hagen, 3.5 5.4 6.8 4. (1 Anal. (.14#11lt4.l1to16- isli-I Biochem; WI, 545, 1976). V. A. Bunnelle VAB/hc V* Pothapraga"d Read aud Reviewed by D WitiLer