Document v6DKbo366zODeNjEVXQ3kE7eR

/IR33S-OIS6 28 Day Percutaneous Absorption Study with FC-99 in Albino Rabbits Experiment No Conducted At: Dates Conducted: Conducted By: 0979AB0633 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 24, 1979 to December 18, 1979 \ /VilGpf ivYii)0o>'____________ ~?// K. D O ' M a i l e d , BS Date Advanced Toxicologist Study Director Reviewed By: dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick K. L. Ebbens, BS Date Supervisor, Acute Toxicology 003748 1. 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 using male and female albino rabbits ranging in body weight from 1.78 to 2.35 kg. (a preliminary rangefinder study was conducted to determine the appropriat dosage level to be used.} The test article was administered by dermal application to ten male and ten female rabbits each at a dosage level of 5000 mg/kg body weight for a 24 hour 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. ' Introduction The objective of this study-- 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.: 0979AB0633, Test Method 699 003749 2. Method ancl Results a Young adult albino rabbits of the New Zealand breed-- were used in this bust. All animal:; 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 ratxon-- 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 404 total body surface area. After administration of the test article, a flexible plastic collar was fitted on each animal and the trunk wra^jped 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 a g- Pel Freez, Inc., Rogers, AR -- Purina Rabbit Chow, Ralston Purina, St. Louis, MO 03750 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, M and 20 day body weights wore 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. C03751 TAULE I ACUTE DERMAL RANGEEINDER TOXICITY STUDY - ALBINO RABBITS with FC-99 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 9B2586 M 9B2589 F 9B2682 E 9U2652 2.45 2.00 2.00 2.00 2.42 1.44 1.63 1.34 0/4 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 F 9B2683 F 9B2655 2.36 2.08 2.28 2.05 2.22 2.17 2.20 2.13 0/4 0 -- Test article was dosed undiluted 003752 TABLE 2 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-99 Mortality and Body Weight Data 5 Dose-- s,,ex (mg/kg) Animal Number Individual Body Weights (kg) _______ Test Day Number__________ 0 7 14 28 Number Dead Percent Number Tested Dead 5000 5000 M 9B3064 2.10 M 9B3067 1.78 M 9B3070 2.25 M 9B3073 2.09 M 9B3065 2.11 M 9B3068 2.14 M 9B3071 2.05 M 9B3075 2.24 M 9B3066 1.99 M 9B3069 2.22 F 9B2920 2.00 F 9B2926 2.07 F 9B2932 2.35 F 9B2938 2.07 F 9B2922 1.97 F 9B2928 2.22 F 9B2934 2.23 F 9B2940 2.01 F 9B2924 2.25 F 9B2930 2.08 1.77 1.77 2.11 1.74 2.08 2.15 2.07 2.01 1.89 2.13 1.77 1.92 2.05 1.63 1.85 1.69 2.15 1.56 2.13 1.99 2.00 1.96 2.25 1.99 2.35 2.48 2.32 2.34 2.19 2.35 2.00 2.21 2.35 1.97 2.05 1.98 2.20 1.52 2.30 1.84 2.25 2.52 2.41 2.65 2.62 2.48 2.47 2.46 2.62 2.30 2.35 2.51 2.22 2.25 2.25 2.35 2.09 2.55 2.08 2.25 0/10 0/100 \ 0 -- Test article was dosed undiluted Necropsy Necropsies performed upon termination of the study revealed no visible lesions 003753 Dose (mg/kg) TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY - ALBINO RABBITS with FC-99 Summary of Reactions Sex Reaction Time of Onset Number Affected Followinq Dose Number Dosed ' Administration Cessation of Reaction Followinq Dose Administration 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 --- --- --- --- --- --- Time of Death Followinq Dose --- --- --- 003754 O' Dose (mg/kg) TABLE 4 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - AL3IN0 RABBITS with FC-99 Summary of Reactions Sex Reaction Time of Onset Number Affected Following Dose Number Dosed Administration Cessation of Reaction Following Dose Administration 5,000 M No significant reactions F No significant reactions -- -- -- -- Time of Death Following Dose -- -- 003755 u inker Experiment. No. : o M '{*Hj^Qb APPENDIX I __ I'KOTOCOl. 8. t e s t : sinylo Dose 20 Day Percutaneous Absorption Study SPONSOR: 3M ___C p m aoS ) CJTDmAiLOiQ._______________________________________ . Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: T_>- C\^__________________________________________ CONTROL ARTICLE: Kl/'A i'Koi'o:;i;i) :;t a k t i n e /c o m i m .e t j o n d a t e o p s t u d y : J-LeTLS__ /.L TEST SYSTEM AND SOURCE: New 'Zealand White Albino Rabbits Pel Proojs, Inc., Royers, Arkansas Sex: .rr r Number: to- iQ Weight Range : 3- :.4>_k 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 the test system for their historical use in dermal absorption studies, ease of handling and general availability. METHOD: 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 S o o Q mg/kg to intact skin coverinq approximately 10% total body surface area. A flexible plastic collar-- will bo fitted on each animal and the trunk wrapped with impervious plastic sheetinq, 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 removedl Prior to th'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. 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 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. W) C 01s Sponsor yfyU_____Jn ?I Date Study Director / 7 a ht Date 003756 Hiker Experiment N o -= , APPENDIX T (Continued) PROTOCOL t\y; y. TEST: Acute Dermal Toxicity Uaiygefinding*-Studv SPONSOR: 3M fl-M S K I SYtT / / Z /'Z/fS.frtfl___________________________________ Divisio CONDUCTED BY: Safety Evaluation Laboratory, Hiker Laboratories, Inc., St. Paul, Minnesot TEST ARTICLE: Z'C_ 'Q Q ______________________________________________________________ _ CONTROL ARTICLE: J ~ PROPOSED STARTING/COMpLETION DATE OF STUDY: fJ/'J<? - / TEST SYSTEM AND SOURCE: New Zealand White Albifto Rabbits' Sex: (y> Cj Pel-Ereez, Inc., Rogers, Arkansas Number ; 2 Body Weight Range: Ol.UECTl.VE: 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 , .-Q'Ti'O , ffYY") 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 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 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 lc d /l4 a u y Date Study Director/ 003757 iti ko r E xperim ent; Mo. APPENDIX 1 ^Concluded) Amendment to Protocol 1. O<r_ -Vo a.-.Ov.LlySl-S O __ b ^ c J __ ______________ Jl'tL p / n f k i l v 'J C o r y td __h=kA __be_. cv-l-t^WoJ__ ______________________________________ _ ID. a fl/vy,^ / "/-h SSttuudy Director^ Date ..-STn~rQu^u-___b L^EAk-.bAaaJx C.loagc)-. ^-?/ Ofr\pCiM v k-_,-.-. Ul i*i\ ^ CQ ) *+'-.'// 6 **-r i ^ i y l _____________________ y / m Study Director t/ sL/ h el Date Study Director Date 6 Study Director Date 7. Study Director Date 8. Study Director Date 003758 APPENDIX II Principal Participating Personnel Involved in the Study il. Name K. A. Mbbon:;, BS Function Supervisor, Acuto Toxicology K. D. O'Malley, BS Dr. V. Pothapragada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory 003759 APPENDIX III Composition Characteristics 12. 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. 003760 APPENDIX IV Quality Assurance Statement 13 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. 003761 InU'i i m IC oi lespoMtlence li. I(. Rickcr l;. I t . <>riffi tli - 22U--2E I-. A. Ubol - 220-2H APPKNMX V K. L. EBBENS - RIKER SAFETY EVALUATION LAB - 203-1 W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E SKIN ABSORPTION STUDIES ON FC-143, FC-95, FC-99, FC-134, FC-135, FC-12R, FC-I29 and FC-9B 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 003762 .Ir : !' li L ii-U .i--i-1-4.---2 2n Vi t u ____5. K. A. Prokop - 2.iG" 2lt I.. D. W i n t e r - 236-2U APPENDIX V (Concluded) COMMERCIAL CHEMICALS DIVISION ANALYTICAL LAB REPORT //I4 6 __ 15. To Fiorn Sub|OC\ Dalo W. C. MCCORMICK - 220-2E-02 V. POTHAPRACAOA AND V. BUNNELLE - 236-3A RIK.ER SKIN ABSORPTION STUDY June 9, 1980 Reference: Commercial Chemicals Division Analytical Request 015669 For lack of time, only a selected set of serumi samples was analyzed. Compound FC-129 TOTAL F > PPm_______ Females Day i Day 28 Males Day 1 Day 28 26.1 69.6 11.4 23.3 FC-134 0.2 18.1 18.8 23.9 FC-- 128 4.4 16.5 1.6 10.5 FC-98 226.4 93.1 271.9 94.3 FC-135 6.9 20.8 2.3 7.6 FC-95 0.9 128.0 10.3 130.2 FC-99 42.5 53.1 111.5 119.8 129.1 72.7 73.5 66.6 Females Males h-tj-jy, i Day 7 , Day 14 10.1 12.1 Day 28 3.5 Day 7 5.4 Day 14 6.8 Day 28 4.6 Mi -i lm| o f Ann I y u I n : O x y g e n llomli/OO T oeltu I quo (.in n l l n l l n l * mul D. F. Hagen, Anal. Blochem; 87, 545, 1978). fJ ^ix.'fiyruJlA.L^ V. A. Uunnelle VAB/hc V. Pothapragada Read and Reviewed by L. y Winter / C 003763