Document 82gyjnROk9wd83JXv1Y7NRjGk

Repeat Application 28 Day Percutaneous Absorption Study with T-2618CoC in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted By: 09790ABO485 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 9, 1979 to December 10, 1979 K. D. O'Mallet@ BS Advanced Toxicologist Study Director Date Reviewed By: dc: M. T. Case K. L. Ebbens W. C. McCormick F. D. Griffith X, a @ @e - K. L. Ebbens, BS Date Supervisor, Acute Toxicology Summary A repeat application 28 day percutaneous absorption study with T-261SCoC was conducted from October 9, 1979 to December 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 lesi( 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 The ob@ective 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. 2@ Riker Toxicity Experiment No.: 0979ABO485, Test Method 699 2. Method and Results Young adult albino rabbits of the New Zealand breeds 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 laboratory ration!i 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 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 a 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 MgAg group received repeat applications on day 1, 5 and 6. 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 containcd in Appendices I - IV. 4. TABLL 1 ACUTE DERMAL RANGEFINDER TOXICITY STUDY ALBINO with T-2618CoC Mortality and Body Weight Data RABBITS a L)ose Sex (mg/kg) Animal Number individual Body Weights Test Day Number 0 14 (kg) Number Dead Number Tested Percent Dead 2000 m 9B2567 m 9B2570 F 9B2562 F 9B2558 1000 m 9B2568 m 9B2571 r 9B2566 F 9B2433 100 m 9B2580 m 9B2583 F 9B2656 F 9B2651 2.44 2.34 2.08 2.24 (8 Days) (4 Days) (8 Days) (1 Day ) 2.15 2.45 2.10 2.32 (9 Days) (9 Days) 1.19 (7 Days) 1.95 2.05 2.28 2.22 2.10 2.05 2.27 2.09 4/4 100 3/4 75 0/4 0 2@Test article was dosed as a water slurry Note: Figures in parenthesis represent time of death I.VAL$LL ACU'VE PLRCU'VANLUUS AJDSORPTION TOXICITY STUDY - ALBINO with T-2618CoC Mortality and Body Weight Data RABBITS a Dosc Sc--x (mg/kg) Animal Number Individual Body Weights (kg) Test Day Number 0 7 14 28 Number Dead Percent Number Tested Dead 100 m 9B2728 2.53 2.35 2.40 2.62 0/10 0 m 9B2731 2-44 2.30 2.58 2.82 m 9B2734 2.53 2.37 2.43 2.67 m 9B2737 2.42 2.22 2.29 2.56 m 9B2729 2.49 2.25 2.32 2.65 m 9B2732 2.47 m 9B2735 2.29 2.25 2.15 2.28 b 2.52 - m SB2736 2.05 1.89 b m 9B2 730 2.35 2.14 b m 9B2733 2.18 1.98 100 F 9B2872 2.64 2.39 2.34 2.43 0/10 0 F 9B2878 2.24 2.19 2.30 2..62 F 9B2882 2.29 1.83 2.06 2.50 F 9B2885 2.17 1.98 1.65 2.08 F 9B2884 2.35 2.27 2.41 2.58 r 9B2880 2.37 F 9B2883 2.39 F 9B2886 2.23 F 9B2876 2.40 F 9B2881 2.53 2.25 2.20 2.00 2.26 2.2@i 2.18 b b b b 2.42 - - Necropsy Necropsies performed on animals upon termination of the study and also at the interim sacrifice period revealed no visible lesions. a The test article was administered as a water slurry b Animals sacrificed on day 14 TABLE 3 ACUTE DEWLKL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with T-2618CoC Summary of Reactions Dose _(mg/kg) 2000 1000 100 Sex Reaction Nurl-berAffected t)wt%ber Dosed Time of Onset @l Following Dose Administration m Hypoactivity 1/2 Lethargy 1/2 Tremors 1/2 Day 7 Day 8 Day 8 F Hypoactivity 1/2 Day 7 m Hypoactivity 2/2 Lethargy 2/2 Day 7 Day 8 F Hypoactivity 1/2 Lethargy 1/2 Emaciation 1/2 Day 7 Day 8 Day 13 m No significant - F reactions noted Cessation of ?.eactionb Following Dose T Administration Fo Day 8 Until death Until death Until death Day 8 Until death Until death Day la Until death a Time Time when when first animal no animal in in the dose group exhibited the reaction the dose group exhibited the reaction No significant reactions TABLE 4 ACUTE DERMAL PEROUTANEOUS ABSORPTION TOXICITY with T-2618CoC sununary of Reactions STUDY - ALBINO RABBITS Dose (mgag) 100 Sex Reaction Time of Onset tiumber I^ffected Following Dose t]tL,%berDosed Administration m No significant reactions noted --- F No significant reactions noted --- Cessation f Reaction Following Dose T Administration F --- No Significant Reactions noted l@ APPENDIX I llsl4.!gLtN,i). Acutu Durinal ToxiciLy llzLne1cfinderStudy-- SPONSOR: 3M CONDUCTED BY: C ,;riilr6i,(,r,114 (- Cw c /)I/r,,iISafety Evaluation Laboratory, Riker Laboratories, Division Inc., St. Paul, MirLnesotz CON'1'1@OL AI<TICLL: I,I(Ul'USLI:)S'YAI@-l'IN(;/CC)ML-ILLT1:ON UIVI!L OL-' STUDY: SY.I@'VLMANU SOUL<CL: New Zealand White Albino Rabbits: Sex: 14ale/Fe=li:@ Number: 1/sex/level Body Weight: 2.00 3.00 kj (.)I)jucLivuu@ Liki.-u;ludy will be to datursaino a dose level range for the Lu:iL ArLiCic fc)r !;ulj:.;(iquLd:ezrimtal LU50 determination. Rabbits wcrt2 t;L-Iected .i.,L;liQ Lc!sL syt;LL:iftulr their sensitivity of response, historical data, case t)f ii.iricil.ia.rjiidUtic!nf!rzka.v1zlilability. Irk-ia(n2imals will be housed tn standard wire-mash cages in temperature and liLunidiLy controlled rooitiswith f-ooda and water offered animal will be at;si.cjn(,a-dnumbered car tag, which will ,Afi:iXeLlLO tll(-O-uLsidL- Of the cacje. The trunk of each ad libitum. Each Tor7resl-@@ond:to a card gnimal will be clipijqd free of 1-iairand the test article placed on the abraded:--surface of the skin tor a 24 hour uxljosure period as single dose levels of 5000 and 2000 my/kg. AfLcr adniinistralion of the test article as a saline slurry, the animals will ljo-r.t:LurtiL-clLo for ;A 24 liour cxi)OSU.CUij-"iod, aftcr witictiLime tile Lcst article will be removed from the dermal surface of the animals. The aiiiinalswill be observed for mortality only for the following 14 days. Putina Rabbit Chow, l@alston Purina, Longitudinal abrasions will be made ttic exi3osure site sufficiently deep suf.L'icient to cause bleeding. St. Youis, Missouri approximately every ten cencimeters to disrupt the epidermal laier, but alonc not Sponsor Date study Dired-tor Data Riker EXPeriment NO.; APPENDIX I (Continued) PROTOCOL 9. UIEST: Repeat Application 28 Day Percutaneous Absorption Study SPONSOR: 3M 0 (*ONI)LICIIIIJ.Y:D -;@IfL'L1y';Valu,iL.ioin.al>oratory,ltikf-.Lraboratories, 'I'ES'IA'RTICLL: Inc., St. Paul, CON'1'1@01. Pl@C)POSL;'DSTAR'I'lN(@/CC)MI)LL'I'IONUATE OF STUDY: ttl-r@ TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Pel-Frocz, Inc., Rogers, Arkansas Sex: M & F Number: 10&10 Body Weight Range: Divisioi-, minnesot" 2.0 - 3.0 OBJECTIVE: 14L..,I:llou: 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 uf lialidiiialr(iJijyullqralavailuiiiiity. 'I*Iiacniinals, t;cluctqd from a larger colony by health and body weight, will be randomly housed in standard wire-mesh cages in temperature and humidity con- Lrolled rooms willi food2;and water offered ad libitum. Fach 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 oOt) mg/kg to intact %;kiiicL)vQr.Lng aliliroxiinately-1-0%total body surface @@rea. 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 weiglit 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 for=lin for possible future microscopic examination. initial, 7, 14, and 28 day body weights will be recorded as well as alny 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 ingestion of residual test article., of the study to reduce oral Sponsor Date Study Dikectot Date 2.3. 4. 5 7. Riker Experiment No.: APPENDIX (Concluded) tum--ridnx--ntto Protocol 10. t7 < 1=0 Study Dirsi@:tor Data <,OQ Study Direc- tor U /7, 1 Date v io/icl Study Director U Date 4-,k Study Di r Date v- Study rA Director 4 Study Di'CeCt4 Date Date Study D;LrectAckk Data Study Ekirector Date APLII-.N)-)EX11 Principal Particieating porsonnal Involved in the Study Nam(2 K. 1-.*bben.,B;S, Function Supervisor, Acute Toxicology K. D. O'Malley, ES Dr. V. I-lothal.)ragada 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. litit.-iItillCut 14. APPENDIX V L. EBBL-NS RIKL:lt SAFETY EVALUATION LAB 203-1 Illy" W. C. McCORMICK - MEDICAL DEPT. TOXICOLOGY SERVICES 220-2E SYIN AIJSORPTION S'rU[)11-.OSN I-C-128. FC-129 ;ind I-C-@)8 JUNL-*27, 1980 FC-143, FC-95, FC-99, FC-134, FC-135, l@lleaseconsider this an authorization for your laboratory to release tlio dermal toxicity/skin absorption studies conducted G.; 2%.:I%e'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. Prelimisiary 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. l'bank you for your patience in this matter. Cl/ WCM:klh 15. Al@Lli@NDIX V (ConCludCI) COMMCIAL CHEMICALS DIVISION ANALYTICAL LAB REPORT #146 TO Ftryn Sut@t@ci Wit.- W. C. MCCOI(MICK - 220-2E-02 V- POTHAPRAGADA AND V. BUNNELLE - 236-3A RIKER SKIN ABSORPTION STUDY June 9, 1980 Vf -w oi. Reference: Commercial 115669 Chemicals Division Analytical Request For lack of time, only a selected set of serum samples was, analyzed. Compound FC-129 FC-134 FC-128 FC-98 FC-135 FC-95 FC-99 PAX 7 10.1 TOTAL F, ppm Famalog Day 1 Day 28 Malec. D!X 1 Day 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 94.3 6.9 20.8 2.3 7.6 .0.9 128.0 10.3 130.2 42.5 53.1 13.1.5 119.8 129.1 72.7 73.5 66.6 Females Males Day 14 Day 28 DeX_ z x 14 T)ny ;8 12.1 3.5 5.4 Me.1loobt,ior Aoijilyosll,: D. F. Hagen, Anal. Blochem; @7, 545, 1978). V. A. Bunnelle VAB/hc V. Pothapragada-- Read and Reviewed by IV. U? WinLer 4