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28 Day Percutaneous Absorption Study with FC-99 in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted By: 0979ABO633 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 24, 1979 to December 18, 1979 K. D. O'kallei, BS Advanced Toxicologist Study Director (741 Date' Reviewed By: dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick K. L. Ebbens, BS Date Supervisor, Acute Toxicology Summary A 28 day percutaneous absorption Study With FC-99 Was conducted from October 24, 1979 to December 18, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota usxnq male and female albino rabbits ranging in body weight from 1.78 to 2.35 kci. (A preliminary rangefinder study was conducted to determine the appropriate dof-;agc1!.(@ve.tLc)13(@u!;(-,d-T)he test article was administered by dermal application to ten male and ten female rabbits each at a dosage level of 5000 mg/kg body weicjl)tfor a 24 tiour exposure period. No mortalities, untoward behavioral reactions or body weight losses were noted during the 28 day study. Necropsies were performed on all animals upon termination of the study and no visible lesions were noted. Preliminary serum analysis (Appendix V) indicates dermal absorption of FC-99 in albino rabbits, however, due to the limited number of samples analyzed by the sponsor, no concrete conclusion may be drawn. Introductiori The objective of this study2@was to determine the percutaneous absorption potential of FC-99 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on October 24, 1979 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. Riker Toxicity Experiment No.: 0979ABO633, Test Method 699 motho(i and Results Young adult albino rabbits of the New Zealand breeda were used in this All. aiiiiiial.w-e;re undc@r quarantinc-. for several days prior to testing wi.tl-oinly animals which apl3cared 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 laboratory ratioii!i with food and water available ad libitum. An initial rangefinding study was conducted using two male and two female for eacli (lo:.;acjlccv(--I. 'i'litcrunk of each animal was clipped free of liair 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 tii(-t@runk 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 exl:losur(-p@eriod (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 maleand10 femaleanimalsfordosingandapplicatioonf thetestarticle 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 afterinitiatioonf theStudy for serum which was frozen for sponsor analysis. After the 24 hour exposure @@-Pel Freez, Inc., Rogers, AR b Purina Rabbit Chow, Ralston Purina, St. Louis, MO 3. 1-icriodthe 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 -1112(11(iiiyI)o(lywciicjiitwsurc recorded (Table 2) as were any pharmaco- Lox.i.c rioL(-,((lluriiictjii(-2-8 day observation period (Table 4). A gross necropsy was conducted on all animals sacrificed on day 28 and all findings rc,cord(--(dTable 2). The protocol, principal personnel involved in the study, comijosition characteristics, and Quality Assurance statement are contained in Appendices I IV. TABLE 1 4. ACU'RL I)EI<MAL i-tANGLI-'INULRTOXICITY STUDY - AL131NO RABBITS with FC-99 Mortality and Body Weight Data Dose a Sex (mg/kg) Animal Number Individual Body Weights Test Day Number 0 14 (kg) Number Dead Number Tested 5000 m 9B2586 2.45 2.42 0/4 m 9B2589 2.00 1.44 F 9B2682 L., I)B2052 2.00 2.00 1.63 1.34 Percent Dead 0 2000 m 9B2592 m 9B2595 F 9B2688 F 9B2691 2.25 1.97 2.35 2.02 2.02 1.71 2.17 2.04 0/4 0 1000 m 9B2587 m 9B2590 r 9B2683 F 9B2655 2.36 2.08 2.28 2.05 2.22 2.17 2.20 2.13 0/4 0 2@Test article was dosed undiluted TAJ3LLI 2 5. ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO with FC-99 Mortality and Body Weight Data RABBITS a Dose Sex (mg/kg) Animal Number Individual Body Weights (kg) Test Day Number - 0 7 14 28 Number Dead Percent Number Teste@f Dead 5000 m 9B3064 2.10 1.77 2.00 2.25 0/10 0 m 9B3067 1.78 1.77 1.96 2.25 m 9B3070 2.25 2.11 2.25 2.52 m 9B3073 2.09 1.74 1.99 2.41 m 9B3065 2.11 2.08 2.35 2.65 m 9B3068 2.14 2.15 2.48 2.62 m 9133071 2.05 2.07 2.32 2.48 m 9B3075 2.24 2.01 2.34 2.47 m 9B3066 1.99 1.89 2.19 2.46 m 9B3069 2.22 2.13 2.35 2.62 5000 F 9B2920 2.00 1.77 2.00 2.30 0/10 0 F 9B2926 2.07 1.92 2.21 2.35 F 9B2932 2.35 2.05 2.35 2.51 F 9B2938 2.07 1.63 1.97 2.22 F 9B2922 1.97 1.85 2.05 2.25 F 9B2928 2.22 1.69 1.98 2.25 p 9B2934 2.23 2.15 2.20 2.35 F 9B2940 2.01 1.56 1.52 2.09 F 9B2924 2.25 2.13 2.30 2.55 F 9B2930 2.08 1.99 1.84 2.08 2@Test article was dosed undiluted Necropsy Necropsies performed upon termination of the study revealed no visible lesions Dose (mg/kg) ACUTE DERMAL TABLE 3 RANGEFINDER TOXICITY ALBINO with FC-99 Swranary of Reactions RABBITS Sex Peacti-on Ilir-7th@AAf-frected tlu7@ber Dosed Time of onset Following Dose Ad,,unistration Cessation of Reaction Following Dose Acl-.i;-sntiration 5,000 2,000 1,000 m No significant reactions F No significant reactions m No significant reactions F No significant reactions m No significant reactions F No significant reactions ----- ------- ----- ------- Dose (mg/kg) ACUTE PERCUTANEOUS TABLE 4 ABSORPTION TOXICITY STUDY with FC-99 Surr,m,aryof Reactions - ALBINO RABBITS Sex Peacti-on Ilu:.-@@-Arffected t]L,:-,.bDeorsed Time of onset Following Dose Admnistration Cessati-on o;-'Peaction Following Dose Aciri;-nitsration 5,000 m No significant reactions F No significant reactions ----- ----- APPENDIX k.iPt@t I- iiiiiL-itNci Hdo(3,3,f, Lt. Single SI,CjlqSOI@: 3M CONDUCTED BY: Dose 28 Day Pvrcutaneous . C t-@r, Or e 11 K@ UtAy@x Absorption -o,@ Safety Evaluation Laboratory, Riker Study Laboratories, TEST ARTICLE: CONTI@OL ARTICLE: I)A'1'1-O,l'-' @j'I'UL)Y: SYS'1'1-"MAND SDURCI-,': Nc@w Zualand White Albino Rabbits I.-'reez,Inc. , l@ocjers, Arkansas Inc., St. Paul, Sex: Number; Weight to-t10 R-ange: Division Minnesota 'I'lioLb,jlctive of this study will I)oteiiLial of the test article in test system for their historical handling and general availability. be to determine the percutaneous absorption albino rabbits. Rabbits were selected as the use in dermal absorption studies, ease of 'l,liacnimals, scl(-!cted from a larger colony by health and body weight, will I)c randomly housed in standard wire-mesh cages in temperature and humidity con- trolled rooms with food2@and water offered ad libitum. I-;achanimal 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 SooC) g/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 ,tdlastic shoetinq, 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 be collected will be removed'. from the orbital Prior to th6'application, blood samoles will 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. a Purina Rabbit Chow, Ralston Purina, St. The collar will be worn for the duration ingestion of residual test article. Louis, Missouri of the study to reduce oral Sponsor Date Study Direct6r Date APPT-NDTX ik tjr Lxl)critiutnL NU. T ((!Ontinu(-d) 'I'i AcuLt-@@P'ONSOR: 3M % 'I-OXiciLy /' . Divi.,.;ion CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: CONTROL ARTICLT',: -L@11,Ali'PING/CUML@LL'I'IDUANTE 01*'STUDY: TL:ST SYSTEM AND SOURCE: New Zealand White Albiho I,Ql-Fruez, Inc. , Rogers, RabbitEi Arkansa* -Sex: Number: Body Weighf Range: 01.IJI-"C'I'IVET:IIL-ObjQCtive Of this study will be to aL.)I.)roximatthee acute dernialtoxicity of the tL,.,a;rtlicle i.nalbino ralibits. Fabbits were selected as the test system for ttic!isrensitivity of response, historical data, ease of handling and general availai3ility. 141:'11'ICiI.): 111)iL. ai)itikals, -.;U'IL-cLcdfroiii a larger colony by hualth and weight, will be randomly housed in standard wire-mesh cages in temperature and humidity controlled rouiiiwsith fodd2@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 Z)-?((", IWA@@- 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 sl)onssr. After administrationof the test article, a flexible plastic collar- will@be fitted on each animal and the trunk wrapped with iiiil)L-rvi1o)ulsasticsheeting which will occlud(-t-he test article. The animal 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- liosureperiod (immediately liostdose 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 stort in the Riker Laboratories Archives, St. Paul, Minnesota. L Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri b The collar will be worn for the duration of the study to reduce oral ingestion of residual test article. Sponsor Date Study Diiectov Da Riker Experiment No.. APPENDIX I @Congluded) luwndinl-ritto Protocol IU. c4,4e L,)/,I' b (."e A-'1 2. -T Study Diiectoxfj Date 3. I-,Itel 4 4@,J t Anl,,_4 5. Study Dii-ect* eC.>e6lf*@ Study Direct5k 0/-7 '7 Date I l(Mnagi-,, to9/g1 Study D.Lrect&i-- Date Study Director Date 6. Study Director Date 7. Study Director Date Study Director Date API@'J-,NI)IXII Principal Participating Personnel Involved in the Studv ZA- Function IIS Supervisor, Acute Toxicology K. D. O'Malley, BS Dr. V. Pothapragada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory 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 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. I 4ul 1 14. 1-*. A. Ul)cl 2,!0-21:. APPI;,Nf)IXV K. I..L.-BBL-NS- I(IKL-SiAtFI:I'IY;VAI,UAI'LIAOBN 203-1 IV. C. Mc(;ORMICK - ML-I)ICALDEPT. MXICOLOGY SERVICES 220-2E SKIN ABSOIZP'RIONS'I'Uf)llO:NS FC-143, FC-95, FC-99, FC-134, FC-135, 1:(:-12R,[:(:-121) -JUNII:27. 1980 llleaseconsider this an authorization for your laboratory to release t)iodermal toxicity/skin absorption studios conducted on the above identioned compounds. It is understood that the studies are being issued in an incomplete forin insofar as the fluorochemical analysi.s of the serum samples have iiot been completed and will not be included in the report. I*li-eliniiiisacrryuin sainl)lcLnalysis indicates absorption of the compounds. *I'heserum data analysis are not sufficient enough to draw aiiy coiicrete conclusions concerning comparitive toxicity. I-lowover, the animal data you have generated addresses this matter in a I)roader eciiitext. it is not certain w)icithe reiiiainingsamples will be analyzed @Lnd tlicir coutpletioiisliould iiut hold up your report any longer. 'I'liziyioiuk for your I)aticiiecin this matte.-. L it, WCM: k Ili IIsit-IIt.a1 4 t IIf**.11.1&IS,'kI, 1' @ -i.1-4.15. 1(. A. 1.. 1). Wlitt.t!r 2@l(J-2u APPENDIX V (Con cluded) comMERCIAL ANALYTICAL CHL141CALS DIVISIUN LAB RF.PORT #146..__. T(; w. C. mCCOItMICK - 220-2E-02 Ff(xrl V. PUFIIAPRAGAI)A AND V. BUNNEL'IJE SubIL-Ct RIKER SKIN ABSORLITION STUDY U,11(! June 9, 1980 236-3A v@Yll. 19do lteferezice: Commercial Chemicals Division Analytical RequeSL #15669 For lack of time. only a selected set of serum ainapleswas analyzed. T(YFAL F, ppm C(xnpound FC-129 1;'C-134 1;*C-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 1.6 271.9 94.3 2.3 .7.6 10.3 130.2 129.1 72.7 73.5 66.6 Females Mal.es Day 7 pay 14 DU 28 L)sx-:@ pay. .14. 1),iy.28 1.0.1 12.1 3.5 5.4 ti.ti ti.0 Mi-flifioefl Aii;ilyjslii: 1filit-(.I(JiiIt(-litil4' Jill4l D. P. Hagen, Anal. Biochem; 8-/, 545, 1978). V. A. bunnelle VAB/hc V. Potliuprugada Read and Reviewed by I L) Wii&Ler PAP