Document 37DpVww7JVMLExNJpvBBGq1DE

0 44t Repeat Application 28 Day Percutaneous Absorption Study with T-2618CoC in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted By: 09790AB0485 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 9, 1979 to December 10, 1979 KO^nfV) Q Q c :-/ K. D. O'kalle^, BS /u h i Date Advanced Toxicologist Study Director Reviewed By : dc: M. T. Case K. L. Ebbens W. C. McCormick F. D. Griffith / f a '* / K. L. Ebbens, BS Date Supervisor, Acute Toxicology 001707 Summary 1. A repeat application 28 day percutaneous absorption study with T-2618CoC was conducted from October 9, 1979 to Decentoer 10, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rabbits ranging in body weight from 2.05 to 2.64 kg. A preliminary rangefinder study was conducted to determine the appropriate dosage to be used in this study. The test article was administered by dermal application to ten male and ten female rabbits each at dosage level of 100 mg/kg body weight for a 6 hour exposure period on five consecutive days a week for two weeks. No mortalities or untoward behavioral reactions were noted during the 28 day study, however, body weight losses were noted in two animals at the end of the study. An interim scarificed was performed on day 14 on four male and four female rabbits and necropsy revealed no visible lesic Necropsies were also performed on surviving animals upon termination of the \ study with no visible lesions noted. Preliminary serum analysis (see Appendix V) indicates dermal absorption of T-2618CoC in albino rabbits, however, due to the limited number of samples analyzed by the sponsor, no concrete conclusion may be drawn. Introduction a The objective of this study-- was to determine the percutaneous absorption potential of T-2618CoC in male and female albino rabbits after repeated application. The study, which was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on October 9, 1979 and completed on December 10, 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.: 0979AB0485, Test Method 699 001708 2. Method and Results Young adult albino rabbits of the New Zealand breed-- were used in this test. All animals 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 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 i the test article was removed from the dermal surface of the animals. This procedure was repeated several times during the first half of the 14 day rangefinder to a further characterize the toxicity of the test article-- . The animals were observed for pharmacotoxic reactions both during the initial exposure period (immediately post dose administration, one and two hours) and after removal of the test article (Daily for 14 days following initial 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 repeat application 28 day percutaneous study. Preparation of the 10 male and 10 female animals for dosing and the actual application of the test article were conducted in the same manner as the rangefinder study. Blood samples were collected from the orbital sinus plexus prior to the initial applica tion and again on days 7, 14, and 28 after initation of the study for Pel Freez Inc., Rogers, AR Purina Rabbit Chow, Ralston Purina, St. Louis, MO Animals from the 2000 and 1000 mgAg dosage groups were readministered the test article on day 6 and 7 while the animals from the 100 m g A g group received repeat applications on day 1, 5 and 6. C 01V 09 |o |CT|(U 3. serum which was frozen for sponsor analysis. After each 6 hour exposure period the test article was removed from the dermal surface. The application procedure was repeated for 5 consecutive days a week for a two week period. An interim sacrifice of four male and four female animals was conducted on day 14 with the remaining animals continuing for observation through the end of the 28 day study. Initial, 7, 14 and 28 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 which died during the conduct of the study as well as all animals which were sacrificed on day 28 and all findings recorded (Table 2). The protocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement arc contained in Appendices I - IV. 001710 TABLE 1 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with T-2618CoC Mortality and Body Weight Data 4 Dose^- _ Ca x (mg/kg) Animal Number Individual Body Weights (kg) Test Day Number 0 14 Number Dead Number Tested Percent Dead 2000 M 9B2567 M 9B2570 F 9B2562 F 9B2558 2.44 2.34 2.08 2.24 (8 Days) (4 Days) (8 Days) (1 Day ) 1000 M 9B2568 M 9B2571 F 9B2566 F 9B2433 2.15 2.45 2.10 2.32 (9 Days) (9 Days) 1.19 (7 Days) 3/4 75 100 M 9B2580 M 9B2583 F 9B2656 F 9B2651 1.95 2.05 2.28 2.22 2.10 2.05 2.27 2.09 0/4 0 -- Test article was dosed as a water slurry Note: Figures in parenthesis represent time of death 001711 TABLE 2 ACUTE PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with T-2618CoC Mortality and Body Weight Data 5 Dose-- 2,,MY (mg/kg) Animal Number Individual Body Weights (kg) Test Day Number 0 7 14 28 Number Dead Percent Number Tested Dead M 9B2728 2.53 M 9B2731 2.44 M 9B2734 2.53 M 9B2737 2.42 M 9B2729 2.49 M 9B2732 2.47 M 9B2735 2.29 M 9B2736 2.05 M 9B2 730 2.35 M 9B2733 2.18 2.35 2.30 2.37 2.22 2.25 2.25 2.15 1.89 2.14 1.98 2.40 2.58 2.43 2.29 2.32 2.28 b b b b 2.62 2.82 2.67 2.56 2.65 2.52 - - - - F 9B2872 2.64 F 9B2878 2.24 F 9B2882 2.29 F 9B2885 2.17 F 9B2884 2.35 F 9B2880 2.37 F 9B2883 2.39 F 9B2886 2.23 F 9B2876 2.40 F 9B2881 2.53 2.39 2.19 1.83 1.98 2.27 2.25 2.20 2.00 2.26 2.27 2.34 2.30 2.06 1.65 2.41 2.18 b b b b 2.43 2.62 2.50 2.08 2.58 2.42 - Necropsy Necropsies performed on animals upon termination of the study and also at the interim sacrifice period revealed no visible lesions. The test article was administered as a water slurry -- Animals sacrificed on day 14 G01712 Dose (mg/kg) 2000 1000 100 TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with T-2618COC Summary of Reactions Sex Reaction Time of Onset sL Number Affected Following Dose Number Dosed Administration M Hypoactivity Lethargy Tremors 1/2 1/2 1/2 Day 7 Day 8 Day 8 Cessation of Reactionb Following Dose Administration Day 8 Until death Until death F Hypoactivity 1/2 Day 7 Until death M Hypoactivity Lethargy 2/2 2/2 F Hypoactivity Lethargy Emaciation 1/2 1/2 1/2 M No significant F reactions noted -- Day 7 Day 8 Day 7 Day 8 Day 13 Day 8 Until death Until death Day 13 Until death _ Time of Death Following Dose Day 4 Day 1 Day 9 Day 7 g- Time when first animal in the dose group exhibited the reaction -- Time when no animal in the dose group exhibited the reaction No significant reactions (-) O' 001713 Dose (mgAg) 100 TABLE 4 ACUTE DERMAL PERCUTANEOUS ABSORPTION TOXICITY STUDY - ALBINO RABBITS with T-2618CoC Summary of Reactions Sex Reaction Time of Onset Humber Affected Following Dose Humber Dosed Administration M No significant reactions noted ... P No significant reactions noted Cessation of Reaction Following Dose Administration Time of Death Following Dose No Significant Reactions noted (-) TEST:" APPENDIX I IM)TuCul, Acute Dermal Toxicity Range finder Study IviKi i Kxj <! iiiu.'iil N<. : (] /J ' , 8. SPONSOR: 3M ________ C a m > n f{r /i c C s M c M tr .') ________________________ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesoti TEST ARTICLE: T - , l 6, t __ _____ ________ CONTROL ARTICLE: r id //-- PROPOSED START1NO/COMPLETION DATE OR STUDY: ^ - TEST SYSTEM AND SOURCE: Now Zealand White Albino Rabbits : Sex : Male/Female. Number : 1/sex/level Body Weight: 2.00 - 3.00 kg o i u i :<;t ivi;: The objuetivu of thin study will be to determine a dose level range for the test article for subsequent dermal LD50 determination. Rabbits were selected as the test system for their sensitivity of response, historical data, ease of handling and general availability. METHOD: The animals will be housed n 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 abraded-- surface of the skin for a 24 hour exposure period as single dose levels of 5000 and 2000 mg/kg. After administration of the test article as a saline slurry, the animals will bo returned to their cages for a 24 hour cxi>osure period, after which time the test article will be removed from the dermal surface of the animals. The animals will be observed for mortality only for the following 14 days. Purina Rabbit Chow, Ralston Purina, St. Louis, Missouri -- Longitudinal abrasions will be made approximately every ten centimeters alone the exposure site sufficiently deep to disrupt the epidermal la/er, but not sufficient to cause blooding. bO Sponsor c. Date Study Director Date C01715 Riker Experiment No .: 0 V 7V/jt i C r / S `a____ APPENDIX I (Continued) "" PROTOCOL 9 TEST: Repeat Application 28 Day Percutaneous Absorption Study SPONSOR: 3M u '0 P~iU,A>,u- i ________________________________ _ Division c o n d u c t e d UY: Safety Evaluation Laboratory, Kiker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: ~ .>.(./<l<',, '._________________________________________________________ CONTROL ARTICLE: ____ k}/_LL________________________________ _ PROPOSED START INO/COMPLET ION* DATE OF STUDY: >1/-?r> - ^ / yo TEST SYSTEM AND SOURCE: New Zealand white Albino Rabbits Sex: M & F Pel-Freez, Inc., Rogers, Arkansas Number: 10&10 Body Weight Range: 2.0 - 3.0 : 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 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 iQO mg/kg to intact skin covering approximately 4.-0% 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 6 hour exposure period after which the test article will be removed. The application procedure will be repeated for 5 consecutive days a week for a two week period with the hair clipping pro cedure repeated as deemed necessary by the study director to insure intimate test article contact with the skin. The doses will be re-adjusted for body weight changes on a weekly schedule during the two week application period. Prior to the first application, blood samples will be collected from the orbital sinus plexus, and again on day 7, 14, and 28 after initiation of the study for serum which will be frozen for sponsor analysis and evaluation. An interim sacrifice of four male and four female animals will be conducted on day 14 of the study with the remaining animals continuing on study until day 28. A gross necropsy will be conducted on all animals which may die during the conduc of the study as well as all animals sacrificed on day 14 and/or 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 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 ingestion of residual test article.. _______________ Ib/r, Sponsor Date i/ h h r r w ' n / n / t f ________ _ Study D i r e c t o r D a t e 001716 Kiker Experiment No. ; ;*7>V/VS^> APPENDIX (Concluded) Ainendiuent to Protocol --------------------- IQ. 1. T V . ..'K j' :-- Vy..uui'j-- t^.i\ 1 .2cs..~ 4r- . I q p s j j /rr^, , It-, W " W t <T,W.--P A !*<$* y. _______________________________________________ K T i ?tV\q QOf c z *V Study Director V Date 2 . T V V. )Ir-v-- iAi.v' i'Ti/v__P~^ Al* T<aAr x c V*. U>________________________ .:l.L .-t : -u J / . J.!.-: f t ii/ A '/l / < .< '* f f o r -\ka. ^ H .a ------------------------------------------------------------------------ ------------------------------------------------------- ________________________________________________ IC.ft D m a O Q t , Study Director 0 V ,< /n 't Date 3. -- fitK,.-.rie-,-v>vV y -- ffvV V)(gr*A c; -- ' k * ^ V C n ** p fre 4-t/> ^ __ duiiVv___:.,11 be_=V < ' A. A t , " M l_____________________________ v: oV\o.t?tV Study Director lo ' j 2 l Date -- L o -- f v c irii)v--~ W ;-- .'S.~ L > --cLka-- b>sA^.ux'iu^,kk-- rTvy. -- </ /H *>~ - ^ r>C.. C^. \/vi' V V <W/vyvA vwr^i'v- r^-u '\xqvV ~lLe ^(xm-6^ ._____ 5---O c v __ iboi__ C-C; o l K . l v . - L.C .^ -ioa___ P ^ p e - 'i A v.-A Ui : . :ii:. \CD dO o Q. SsStudy Director ' % h /7^ Date V ]-u-V >S ^ I dry. (> K ,?OOn J/oce /<00 llc y o C v A V A f-n-A U ^. r tv ^ c j I V y f l t,.r 'p n v - 'W tv ^ 6 -_T^' Study**4 a <j4 i fD\ *irectAor> Ww Date ^.r-luly__ u -i. / ( k v <l/ovj<V ft.', <:.. \ S z i / - o< .S/..// 3- Ck. M-._r> Mor,-- : 1 Study Direct^ Date 7 *__-LLVS-^S_---_----V- ) Wl.`-Af1l TV__D>Vvviitt tt ll. AIMsiPO_-- Ai], ,CwOiii-fSXL.\ >QUcL<li^<i.WV-'.y .itfUBttttqjar O*s>/1f1___ v C-kci.^c t? /1____ Arc ^ . ,..ta ,.i__ liA o -v C i^ i-O __ t o ___/S. Cl C '^ f L L e y C n ^ j__r.r..*1k\-X >1 .'\ll-y.A- '\'m ?vw V. Study DirectI M13-, i Date 8. Study Director Date col'll7 AP PUNIIex ri Principal Participating Personnel Involved in the Study 11 amo K. L. h'bbcm;, DS Function Supervisor, Acute Toxicology K. D. O'Malley, BS Or. V. Pothaprayada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory C01718 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. C01719 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. 001720 Intern.W C oiicsimmhIcim. 14. APPENDIX V yi // / / lo L. EBBENS - RIKEE SAFETY EVALUATION LAB - 203-1 f'C" W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E `Jlit)(-<.t SKIN ABSORPTION STUDIES ON FC-143, FC-95, FC-99, FC-134, FC-I3S, FC-128, FC-121) and FC-98 1 IN ' JUNE 27, 1980 am Please consider this an authorization for your laboratory to release tlio dermal toxicity/skin absorption studies conducted o.: ibe 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 scrum 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. I-' WCM:klh , 001721 lili/Mlil4.<M".|>>III I- 15. APPENDIX V (Concluded) COMMERCIAL CHEMICALS DIVISION ANALYTICAL LAB REPORT #146 To From SuDieci uio W. C. MCCORMICK - 220-2E-02 V. POTHARRACADA AND V. BUNNELLE - 236-3A RIKER SKIN ABSORPTION STUDY June 9, 1980 Reference: Commercial Chemicals Division Analytical Request #15669 For lack of time, only a selected set of serum samples was ' analyzed. Compound TOTAL y. PP__ Females Da^ 1 Day 28 Males Day 1 Day 28 FC-129 26.1 69.6 11.4 23.3 FC-134 FC-- 128 0.2 18.1 4.4 16.5 18.8 1.6 23.9 ID.5 FC-98 FC-- 135 FC-95 226.4 6.9 0.9 93.1 20.8 128.0 271.9 2.3 10.3 94.3 7.6 130.2 FC-99 42.5 53.1 111.5 119.8 129.1 72.7 73.5 66.6 Pernales ____ Males Day 7 . Day 14 Day 28 DSX-J. Day 14 Dny 28 FC-143 10.1 12.1 3.5 5.4 6.8 4.6 Mi-i Ik h I of Ann IyitIh : Oxygen lUimli/CC (.Ion IU'1 lnlf nml D. P. Hagen, Anal. Biochem; 87, 545, 1978). * T C fjt y&JU*vruJjLtV. A. Bunnelle VAB/hc f-id t.J\_ V. Fothapragada Read and Reviewed by l Uy Winter 001722