Document b5OGK6Lok9Ym2Q172wXz1ObYD

* T -H *)g o 28 Day Percutaneous Absorption Study with FC-98 in Albino Rabbits 'r e c ' AL.- f i W t \\ ~\0 X.I ' L LtX ' Experiment No Conducted At: Dates Conducted: Conducted By: 0979AB0630 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 25, 1979 to December 17, 1979 K. D. O 'MalleyO BS Advanced Toxicologist Study Director 3/.. fa 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 1. A 28 day percutaneous absorption study with FC-98 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 weights from 1.88 to 2.30 kg. The test article was administered by dermal application to ten male and ten female rabbits each a dosage level of 5,000 mg/kg body a weight for a 24 hour exposure period" No mortalities, untoward behavorial reactions or body weight losses were noted during the 28 day 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-98 in albino rabbits, however, due to the limited number of samples analyzed, no concrete conclusion may be drawn. ! Introduction The objective of this study^ was to determine the percutaneous absorption potential of FC-98 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., 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. a A preliminary rangefinder study was conducted to determine the appropriate dosage level to be used in this study, b Riker Toxicity Experiment No.: 0979AB0630, Test Method 699 2. Me Uiud a Young adult albino rabbits of the New Zealand breed- were used in this test. All animals wore hold under quarantine for several days prior to testing wiuli only animal.:; 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 :*i*- uiid the test article placed on the surface of the intact skin which covered approximately 40!t total body surface area. After administration of the test article, a flexible plastic collar was fitted on each animal and the trunk wrapiped with impervious plastic sheeting which will occlude the I 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 Frccz, Inc., Rogers, AR lJurina Rabbit Chow, Ralston Purina, St. Louis, MO <Ol-Ol 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, i'l and is day body weiyhts 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 X - IV. TABLE 1 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-98 Mortality and Body Weight Data 4. Dose^(mg/kg) C,,gv Animal Number Individual Body Weights (kg) Test Day Number 0 14 Number Dead Number Tested Percent Dead 5000 M 9B2599 M 9B2602 F 9B2617 F 9B2614 2.37 2.41 2.42 2.15 2.53 2.62 2.31 2.52 0/4 0 1000 M 9B2605 M 9B2608 F 9B2618 F 9B2621 2.22 2.47 2.25 2.35 2.51 2.55 2.16 2.45 0/4 a_ Test article was dosed as a suspension in water TAI-U.K 2 ACUTi: PERCUTANKOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with FC-98 Mortality and Body Weight Data 5. Dose^ Cny (mg/kg) Animal Number Individual Body Weights (kg) _______ Test Day Number__________ 0 7 14 28 Number Dead Percent Number Tested Dead 5000 M 9B3041 2.16 M 9B3047 2.30 M 0113053 2.16 M 9B3059 2.15 M OU304'' 2. 3n M 9B3049 2.11 M 9B3055 2.19 M 9B3061 2.18 M 9B3045 2.30 M 9B3051 2.22 2.58 2.03 2.13 2.10 2.15 1.96 2.22 2.22 2.33 2.15 2.47 2.27 2.45 2.33 2.47 2.11 2.47 2.31 2.52 2.38 2.68 2.70 2.54 2.70 2.37 2.75 2.46 2.79 2.70 2.63 0/10:0 5000 F 9B2921 2.25 F 9B2927 2.12 F 9B2933 2.18 F 9B2939 1.99 F 9B2923 2.08 F 9B2929 1.88 F 9B2935 2.11 F 9B2941 2.02 F 9B2025 2.12 F 9B2931 1.94 2.03 2.00 1.87 1.72 1.99 1.72 2.14 2.13 1.98 1.94 2.25 2.29 2.01 2.09 2.30 1.90 2.33 2.25 1.70 2.14 2.66 2.78 2.37 2.42 2.65 2.21 2.85 2.48 b 2.37 1/10 10 -- Test article was dosed as a suspension in water -- Animal sacrificed on day 14 due to accidental back injury inflicted during the day 7 bleeding period Necropsy Necropsies performed on all animals upon termination of the study revealed no visible lesions. Animal 9B2925 which was sacrificed on day 14 due to posterior paralysis, also revealed no visible lesions. Dose (mg/kg) TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-98 Summary of Reactions Sex Reaction Time of Onset Number Affected Following Dose Number Dosed Administration Cessation of Reaction Following Dose Administration 5000 1000 M No significant reactions noted F No significant reactions noted M No significant reactions noted F No significant reactions noted -- ---- -- -- -- ---- -- -- Ti-e of Death -- -- -- Dose (mg/kg) TABLE 4 ACUTE PERCUTANEOUS TOXICITY STUDY - ALBINO RABBITS with FC-98 Salary of Reactions Number Affected ot 5000 M No significant reactions noted F No significant reactions noted ___ ___ ----- Kikci Experiment Nu.: QH~ IM HtOb AI'I'END [X T l'KU'i'OCUi, 8. TEST: Single Dose 28 Day Percutaneous Absorption Study SPONSOR: 3M _____ C.gx~r>.rr\px-c io.Q C.^Prrw'c n Q _____________________ ________ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: \"C - Lo-V ^5 CONTROL ARTICLE: _ (O ft ~ ~~ Pi-iOPOSED STAKTiNL/COMPLETlON DATE OE STUDY: \|_ -jq / (.^ t e s t SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: ~ " m 4.p "----' Jel l-'reez, Inc., Rogers, Arkansas Number: IO |Q Weight Range: 0 - 3 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 numoered 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 PyOOP mg/kg to intact skin covering approximately 10% total body surface area. A flexible plastic collar-- will be fitted on each animal and the trunk wrapped with impervious elastic 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 samules 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 ofliver, 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. S . j-j 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 C .\ rY \ r ( Sponsor .(/ X q-l " A f n r\ Date Q. Study Kiktji Exper imeni No .i ^ a / / / / ) / / APPENDIX T (Continued) I'KU'IX'COl. 9. 'll.ST: AcuLu berjjial Toxicity .Rangefinding Study. SPONSOR: 3M___ ( j n / y y? ( r r/ crr / / y ? / / r S T # _____________________ Divi TEST^ARTICLE: M o r a t o r y , Hiker Laboratories, Inc., St. Paul, Minne CONTROL ARTICLE": / .'/ J ` ------------------------ ----------- ------ ------------ l`K(H'UEElJ ETAKTINC/CUMPLETIUN JjaTE OF STUDY: iJ.SI SYS iKM AND SOURCE: New Zealand White Albino Rabbits Sex: r f ^ i y Pel-Freez, Inc., Rogers, Arkansas Number : ' Q j j Body Weight Range: in OBJECTIVE : The objective of this study will be to approximate the acute dermal toxici O, the e,L article in albino rabbits. Rabbits were selected as the test system for their sensitivity of response, historical data, ease of handlin and general availability. anaxin MI.IIKJU: The animals, selected from a larger colony by health and weight, will be cTMon " -" "" V S wire-" sh " 9es in temperature .d u^iditv controlled rooms with food- and water offered ad libitum. Each *,,<1 , oe assigned a numbered ear tag, which will cors5id to a card a f ^ x e d to the out^ d e of the cage. The trunk of each animal will be clipped free of delg"f o -f/iff " o / r n PlU , ? h * 5ie T a, e th in" Ct sk" " ning 2s ssrtLsS S B in ih V i approximated. All raw data and the final report t i l l L the Riker Laboratories Archives, St. Paul, Minnesota. st, - Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri ' g e V o i 1" i e i i d ^ l ^ t V t S e ^ 10" f ^ *tUdy t0 1 in- M Sponsor Date Study Difectaf^ / 1 . ")k... '-4-. i cV~".</:' ') . RlJcer Experiment No. : APPENDIX I (Concluded) Amendment t.o. Protocol C-. Vv.- ^ -Kio d - O O o T r a / H r \~\V^<0 Pu \ \Wjt .Wl.vivi.^iUwr^W ^ 2 ^ \ k -,c w '0 I:-<-> 1 It-N Study Director^ ; V - ___U M f O o v f\jU0 tb t\l 1 \sA^SL. ^^^-b.xrP.Kn "fai# Date 3 \\. /.i - '-Uivn` Xi VovyWjiiiM Study Director f $52/? Date ( 0ViX^''.tbov\(liAq ravinv\).vtJl Im -Uu ? tsQclbu ;a--\]\: '> k ) \ x \ b \ Vk u O Q K o . rl.nmnyl) . Q 'Tu R oi/ C C ' ' ) >'i) v i r a ,i .., 4 . W-i v, '0.-.\ { \.y\' U \,* P.1. , 'J \ :>,%:V> \ Jl ill') ^a Vu c ^ a ~fe> 1- % - S lr<^ "M r ) Date ftvoW 5. Uv. 'j ~V~> r> .)r,0f..,, f.)\j ]\ \ 11: i \ i .AA 1))Oj'/-) J_sL VM'-> -A* pcvd'1K 0 P iio ftvVl nOUiU^' Stl--ud"y* DT"i`r-e-ct-oo;il i l/ .9 o h 0i ' -Date A X O T 0 A i A ,nL O AArO , o k h ^ ( h A W r Q PC# 10. Study Director Date 7. -1Study D irector Date 8. Study Director Date APPENDIX II Principal Participating Personnel Involved in the Study li. amo______________________________________ Function ____________________ K. I,,. bbbons, bs Supervisor, Acute Toxicoloyy K. . O'Malley, BS Dr. V . Pothaprayada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory 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. 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, ana tne facilities are examined by Laboratory Quality Assurance on a three month schedule. K IiK j I 1' *i iM il 11 / j u i. A. Ubol - APPENDIX 5 : K. L. EBBENS - K IKEK SAFETY EVALUATION LAB - 203-1 W. C. McCORMICK - MEDICAL DEFT. - TOXICOLOGY SERVICES - 220-2E .... re-u j - * - = - - * * . * - * . JUNE 27, 1980 14. 3M I'leasc consider this ;m the donnai toxicity/skin mentioned compounds. authorization for your laboratory to absorption studies conducted on the release above f 2 isr-" have not been completed and will not b e t n c l u d J L r ^ r e ^ t iie" ^ : pi : t n ; i r isindicates context. It is L t Z r t Z T Z Z t and their comp, ,, i o n ^ rC'SCS * "etter in a broader Thank you for your patience in this matter. WCM:klh liiliiil.il(.di ic:,|M,, |<11, I li .I K. A. I'i'(jku|i - 2.I0-7'I I.. U. Wi il l. .i - 230-28 15. APPENDIX* 5 (Concluded) COMMERCIAL CHEMICALS DIVISION ANALYTICAL LAB KKPORT 014G lu f .iyn xioieci Um- U. C. MCCORMICK - 220-2E-02 V . POTHAPRACADA AND V . BUNNELLE - 236-3A K1KEK SKIN ABSORPTION STUDY June 9, 1980 Reference: Commercial Chemicals Division Analytical Request If 15669 For lack of time, only a selected set of serum samples was analyzed. __________ TOTAL F. ppm_______ Compound FC-129 FC-134 FC--128 FC-98 FC-135 FC-95 FC-99 u l 2 . Females Day 1 Day 28 26.1 69.6 Males D*y * Day 28 11.4 23.3 0.2 18.1 18.8 2.3.9 4.4 16.5 1.6 10.5 226.4 93.1 271.9 94.3 6.9 20.8 2.3 7.6 0.9 128.0 10.3 130.2 42.5 53.1 111.5 119.8 129.1 72.7 73.5 66.6 Females Males Day 14 Day 28 Dny 7 Day 14 Day 28 FC-J.4 3 i.0.i 12.1 3.5 5.4 6 .8 4.0 M.-1In>il if An;i 1y11111 : O" x"y/jI'.. 'e"n .H. o. mi nlin // C. .C. 'Ti c.r- .. '.lmini li(i||ii iiie' V(..1.M(iJlIIl I11l1e*iIIlIu!l 1l -* njimihl I D. F. Hagen, Anal. Biochem; 8 7 , 545, 1978). -n/nuM l V. A. Bunnelle VAB/hc 'jO t*J\ V. l'othapragada Read and Reviews