Document YrZBXxyknkqaD3G8p1ODBXr8k

28 Day Percutaneous Absorption Study with FC-129 in Albino Rabbits Experiment No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick 0979ABO627 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota October 24, 1979 to December 18, 1979 K. D. O'Malleo, BS Advanced Toxicologist Study Director bate K. L. Ebbens,-BS Date Supervisor, Acute Toxicology Summary A 28 day percutaneous absorption study with FC-129 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 1.75 to 2.42 kq. The test article was administered by dermal application to ton male and ten female rabbits at a dosage level of 5,000 mg/kg body weight for a 24 hour exposure period4 Six mortalities were noted'w.hi'choccurred between days two and three. The untoward behavioral reactions which were noted during the 28 day study consisted of lethargy, hypoactivity, prostration and blood was noted the urine. Onset of the reactions occurred from day 1 to day 6 and all reactions subsided by day 7 or deatli precluded recovery. Body weight losses were noted in two of the animals which survived the observation period. Necropsies of animals which died acutely, generally revealed pale, mottled livers and blood in the urine with one animal exhibiting a dark green spot on the brain. Necropsies were also performed on animals which survived the study period and revealed no visible lesions, with the exception of one animal which had an atrophic spleen. Preliminary serum analysis (see Appendix V) indicates dermal absorption of FC-129 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-129 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on October 24, 1979 A preliminary rangefinder study was conducted to determine the appropriate dosage level to be used in this study. b Riker Toxicity E:@cperiment No.: 0979ABO627, Test Method 699 2. and completed on Decombor 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. Method Young adult albino rabbits of the New Zealand a breed-@--were 3. used in this tc.,@,t. All att:Littzti:w;t--rL,liuld under tluarant;ine for sovaral c!ays Prior to tf--Stincj w.i.l:Cl)kIIIYz@allililcWiAlli.:Cl;a aL.)lj4Laretdo bu in good h(--althand t;uitable as tlst aiiiinala-t- the iriiLiaLionof the study used. The rabbits were housed individually in stainless steel, wire-bottomed cages and maintained on a standard laboralory ration!iwiui Eood and water available ad libitum. An initial rangefinding study was conducted using two male and two fem-le rabL)Itsfor cactidosage level. 'riiterunk of each animal was clipl.)Af-rdee 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 Lest article, a flexibleplastic 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 aniinals. 'rheaniinalswere observed for pharmacotoxic reactions both during th,eexposure period (immediatelypost dose administration, one and two hours) and after removal of the test article (daily for 14 days followingdose admin- istration)with all reactionsrecorded (Table3). Initialand 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 Pel Freez, Inc., Rogers, AR Purina Rabbit Chow, Ralston Purina, st. Louis, Mo 4. 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, 14 and 28 day body weights werc@ recorded (Table 2) as were any phamacotoxic 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). .Vheprotocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement are contained in Appendices I IV. 5. ACUTE DERMAL RANGERINDER TOXICI'I"I STUDY - ALBINO RABBITS with FC-129 Mortality and Body Weight Data Dose a (mg/kg) Sex Animal Number Individual Body Weights (kg) Test Day Number 0 14 Number Dead Number Tested 5000 m 9B2593 2.22 1.29 0/4 m 9B2591 2.19 1.44 F 9B2689 2.07 1.41 L., 9B2646 2.26 2.03 Percent Dead 0 2000 m 'JU2594 m 9B2597 I., 9B2684 r 9B2687 2.10 2.09 2.17 2.02 1.76 2.00 2.14 1.87 0/4 0 1000 m 9B2574 m 9B2577 F 9B2690 F 9B2693 2.20 2.29 2.37 2.16 2.31 2.37 2.24 2.18 0/4 0 Test article was dosed undiluted 6. ACUTE PERCU2ANLOUS ABSORPTION TOXICITY STUDY - ALBINO with FC-129 Mortality and Body Weight Data RALBBITS a Dosc Sax (mg kg) Animal Number Individual Test 0 7 Body Weights Day Number 14 (kg). 28 Number Dead Number Tested Percent Dead 5000 m 9B3056 2.20 1.82 1.78 2.18 1/10 10 m 9B3062 2.40 1.97 2.11 2.41 m 9B3057 2-42 2.14 2.43 m 9B3063 2.10 (2 Days) ---- 2.7S ---- m -9B3072 1.75 1.91 2.12 2.44 m 9B3077 2.04 2.04 2.05 2.30 m 9B3032 2.04 1.59 1.73 2.18 m 9B3038 2.38 2.15 2.37 2.45 m 9B3033 2.36 2.23 2.23 2.60 m 9B3039 2.28 1.98 2.25 2.42 5000 F 9B2985 2.23 (3 Days) ---- ---- 5/10 50 F 9B2991 2.17 (3 Days) ---- ---- F 9B2936 2.23 (2 Days) ---- ---- F 9B2942 2.00 1.61 1.56 F 9B2960 2.37 (2 Days) ---- 1.84 ---- F 9B2966 2.07 1.70 2.05 2.43 F 9B2955 1.87 1.89 2.15 2.44 F 9B2967 2.04 1.81 2.05 2.33 F 9B2937 1.98 1.72 2.04 r 9B2943 2.05 (2 Days) ---- 2.32 ---- 2@Test article was dosed undiluted Necropsy Necropsies performed on animals which died acutely, generally revealed pale mottled liver and blood in urine, with one animal having a dark green spot on the ;brain. Animals which were sacrificed upon termination of the study revealed no visible lesions, with the exception of one animal which had an atrophic spleen. ACUTE DMIAL TABLE 3 RANGEFINDER TOXICITY STUDY with FC-129 Sw.mary of Reactions ALBINO RABBITS Time a Ci@set Cessation of zeaction Dose (mg/kg) Sex Pzaction tiurber Affected Following Dose tit,;@,beDrosed Ad.-.unistration Following Dose Ti Adn.;-nistration Fo 5000 2000 m Hypoactivity 2/2 F No significant reactions m No significant reactions p No significant reactions Day 9 --- until termination --- 1000 m No significant reactions p No significant reactioris --- a Time when first animal in the dose group exhibited the reaction Time when no animal in the dose group exhibited the reaction ACUTE PERCUTANEOUS TABLE 4 ABSORPTION TOXICITY STUDY - ALBINO with rc-129 Su:7.naryof Reactions RABBITS Time of onset Cessation of Reaction Dose (mg/kg) Sex Peacti-on tiur,.beArffected t]L,:-tbeDrosed Following Dose Ad..mnistration Following Dose T Ad.-,tinistration F 5,000 5,000 m Hypoactivity Lethargy Prostration Blood in urine F Hypoactivity Prostration Blood in urine 1/10 2/10 1/10 1/10 4/10 1/10 2/10 Day 6 Day 5 Day 1 Day 1 Day I Day 1 Day I Day 7 Day 6 Until Until death death Day 3 Until death Until death a Time when first animal in the dose group exhibited the reaction Time when po animal in the dose group exhibited the reaction l@ikt!r 1-.xl)criitiL-Niu'.i:L APPENDIX 1 9. P)tUllOCOL Single Dose 28 1)ay Percutancous Absorption Study SIIONSOR: 3M CONDUCTED BY: Safety TEST ARTICLE: Evaluation Laboratory, Division Riker Laboratories, Inc., St. Paul, Minnesota CONTROL ARTICLE: lll@Ol'OSI-f*;.'II.')AIVI'IN(;/COMIILL-I'I:)IAO-Ni'OlF..'STUUY: 'I'LS'SiYlSTEM ANL) SOURCE: New Zealand White Albino Rabbits llu.L-'rcuz,Inc., Royers, Arkansas Sex. F Number; 1-0/to Weight Range: Q -*2,k.*- OU,IL-'.C'rlVl-@'':Vliuobjective of this study will be to determine the percutaneous. absorption 1.30tentiaolf the test article in albino rabbits. Rabbits were selected as the LusL sysleinfor their.historical use in dermal absorption studies, ease of handling and general availability. Mt-"I'l(Ot): 'PliL-aiii.iiiztl:;, E'roiniA laryor colony by h(.-altahnd body weight, will b(-- randoinly housed in standard wire-mesh cages in temperature and humidity con- trolled rooinswitlifood@land watl@roffered 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 w4XDQ ui?/kgto intact skin coverinq approx3mately 10% total body surface area. A flexible plastic collarb will be fitted on each animal and the trunk wrapped with impervious olastic 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 removed. Prior to lihO.'application,b,lood 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. 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. Louis, Missouri The collar will be worn for the duration of the study to reduce oral ingestion of residual test article. Sponsor It,-Pb If 'Date I (&IA Study Direls@r APPENDIX i-*.xibecittitN:ui.iL. 17VI(IIJ06r I (Continued) '@r!7.STA:cute Dermal Toxic ty ii cjefinoi!,g/,tldy SPONSOR: 3M CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, TEST ARTICLE: CONTROL ARTICLF,-. I'liUPOSLU STAI<TING/ U I TEST SYSTEM AND SOURCE: riUN Now Zealand Pul-Preez, White Inc., Albifio Rogers, Rabbiti Arkansa* Sex; Number;' Body Wei-g"-IfRia-nge: Division Minnesota OBJECTIVE: ML*TiiOD: 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. The animals, su-lected from a larger colony by health and weight, will be randomly housed in standard wire-mesh cages in temperature and humidity controlled rooms with focat 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 mg/kg, however, if these dosage levels do not adequatbly 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 receiveck) from the sponspr. After adminiitration 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 animal5 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 (LDSO) of the test article will be approximated. All raw data and the final report will be store in the Riker Laboratories Archives, St. Paul, Minnesota. 1 Purina Rabbit Chow, Ralston Purina, St. Louis& Missouri b The collar will be worn for the duration of the study to reduce gestion of residual test article. oral in- Sponsor Date Study Dikocty Dat APPENDIX Amendment Riker I (Concluded) to-Protocol ExperimentHo. 3cR-)9 Rbo6-"Il 'titNk.'V 2. vi- Ecc) Och,4 study DLiectox4i Date Study Director Date Study Director 4. tlAAI-&@ A kNA 0,,AA c Study Director Date study Director Date 6. Study Director Date 7. Study Direct= Data S. Study Director Data APPENDIX Il Principal Participating Personnel Involved in the Study 12. ---Name K. L. I"@,bbon.--B;S, K. D. O'Malley, BS Dr. V. Pothapragada G. C. Pecore Function Supervisor, Acute Toxicology Advanced Toxicologist Study Director Connercial Chemicals Chemist Supervisor Animal Laboratory APPENDIX 111 13. 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. 14. APPENDIX IV ouality 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.