Document v1QKn49yvRBygmvqDM946ZDzY

M a ,se _ 6s ~5 PFOS 3Pharmacokinetic - 000163 * l-`i ci O 28 Day Percutaneous Absorption Study with FC-98 in Albino Rabbits r e c'A Mti i i t w T 6 )L\C ctifyf 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 IQ _____ Ifl'lSL K. D. 0 'MalleyO 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 000170 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 b 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 000171 2. Method a young adult albino rabbits of the Mew Zealand breed-- were used in this Lo.st. All animals wore held under quarantine for several days prior to testing with only iiniiiML:; winch 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*- 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 and 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 tlie trunk wrapped 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 a k Pel Freer, Inc., Rogers, AR -- Purina Rabbit Chow, Ralston Purina, St. Louis, MO 000172 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 2u day body weiyhts were recorded (Table 2) as were any pharmacotoxie 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. 000173 TABLE 1 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-98 Mortality and Body Height Data 4 Doso" (mg/kg) ,, Coy 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 000174 TAWJ.K 2 ACIJTF PERCUTANEOUS ADSORPTION TOXICITY STUDY - ALBINO RABBITS With FC-98 Mortality and Body Weight Data 5. Dose^- Scx (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 9D3053 2.'.16 M 9B3059 2.15 M mi304'5 2. 30 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 2.63 2.68 2.79 2.54 2.79 2.37 2.75 2.46 2.79 2.70 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 9U2925 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 -- 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. 000175 Dose (mg/kg) TABLE 3 ACUTE DERMAL RANGEFINDER TOXICITY STUDY - ALBINO RABBITS with FC-98 Salary of Reactions Sex Reaction Time of Onset Marier Affected Following Dose Humber 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 ----- ----- ------ ----- Time of Death Following Dose ----- ----- 000176 O Dose (mg/kg) TABLE 4 ACUTE PERCUTANEOUS TOXICITY STUDY - ALBINO RABBITS with FC-98 Summary of Reactions Sex P^action Time of Onset Number Affected Following Dose Number Dosed Administration Cessation of Fraction Following Dose Administration 5000 M No significant reactions noted F No significant reactions noted -- "" -- Time of Death Following Dose -- "1"-- 000177 -o Kiket Experiment No. : QM' lM APPENDIX I -P-U-U--T-U-C-U-E bp Q_ TEST: Single Dose 28 Day Percutaneous Absorption Study SPONSOR: 3M _____ C_ay<-rsr\frx-g TryQ C j f t w c a Q __________________________________ _ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota TEST ARTICLE: \r C- _________ L q -V ^15________________________________________________ CON'I'ROL ARTICLE: __ /jft_______________________________________________________________ _ PROPOSED START INO/COMP LET!ON DATE OP STUDY: V\- 1 <1 / )TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: r O 4- \- Pel Freoz, Inc., Rogers, Arkansas Number: IQ + 0 Weight Range: 0 " 3 kA 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 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 tost article applied as a single dosage of <=% n O Q mg/kg to intact skin coverine approximately 10% 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 24 hour exposure period after which the test article will be removed. Prior to t h e '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. Va1> C \r'C\r(~ Sponsor .{/, Xo/ 1>Ajn'\ Date Study 8 S T C 0 P y A W ,M S [ 000178 Kl.ki.-i.' Ex pec uuwllL No . :{ ^ j / / / )/ f i * ' APPENDIX T (Continued) PKim'KXH. TEST: Acute Uorytul Toxicity .Hunyefj.ndiiiy Study, s p o n s o r : 3m r f r z n ? ? ! r r / r r f fs ? M Y r s r / 9__________________________________ _ Divi CONDUCTED BY: nation laboratory. Hiker Laboratories, Inc., St. Paul, Minne TEST ARTICLE: s _r_r_>__y_-_ _%_____ CONTROL ARTICLE: /?J/J PRO PUL ED STAKTINC/CUMPLET 1UN DATI-; UK STUDY TEST SYSTEM AND SOURCE: New Zealand White Albino Rabbits Sex: jy Pel-l'reez, Inc Rog-e-rs, Arkansas Num'1--be-r-: 'X ? jp Body Weight Range: Q \ r ii c { o b j e c t i v e .- The objective of this study will be to approximate the acute dermal toxici of the te.*Jt article in albino rabbits. Rabbits were selected as the test system for their sensitivity of response, historical data, ease of handlit 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 aa libitum. Each animal wil 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 sing dosages of ,t. y ( . (i('iC ) mg/kg, however, if these dosage levels < not adequately characterize the toxicity of the test article, additional animals will be administered the test article at supplemental dosage level: Any additional dosage levels will be documented and filed with this protocc 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 anin 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 animal 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 st< 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. f i) f) Sponsor Date Sty^?^ BEST COPY AVAILABLE 000179 RiJeer Experiment No. : APPENDIX I (Concluded) Amendment t.o. Protocol i >---VV * f ^ n C v ^ Vu-> '~tVo d ,,0 0 0 -mo/ W'iCV> Ir C Ov.M;1) V-.. -Vv ^(H>\ V\v> .A '. . CmA-v n. .Vv~lVW*(, .C\ I-iVin. ` \\l il s(\ \ l ' l A . . / A J A a .A OINAA//*" -E2Mb022: 10. 2 vU') i T'.'.... cw-i> W . \y> Ac-wv^ y. l.AAAfQo.^ rr-^ K Pfrmlliky SSttuuddy Directtoorr^^" "`IsHla Datee ( t o w M v - U v > ^ \ ^ ; >d)oDtrjbt.rQ t h d fc> til r\~\ncp.y l-* h V-O ,- Study Director <? ^/cfah0! Date 3 . ' \\., />!-A'- tiresc^- ( ),\..--\k \ (O.VxV-hA, W i M > U o . A . r \ r r f V L r i "fex X ( 1'\x`1'"'*t.f 1 )' 1'*) \f \. < xi .V t M Study Directory 4 . \V-1 v>}<* \i,,\\ '\`..v'V(/. . 9y A/ufy ^ I% - ^ 0 IfO 'V-'-J \:,a A - A . \ HW) ^a Vu O^JVS C O^J) * "/'y/r) Date U.V j ca fip 'lo ^ Study Direct "//-H Date 5. W , . 3 \-> n InOf^A \,w mpeftfr K X C T Q A A A a - n OiArO ____- i w C P w w g g ^ fe u & r x o K t ! LO .O ifin x c O o d / ~fr\ ^^M rtU ii^ -7//0h Study Director {J Date 6. Study Director Date 7. * Study Director Date 6. Study Director 3 EST COPY AVAILABLE Date 000180 APPENDIX XI Principal Participating Personnel Involved in the Study 11. Name____ K. !.. Bbben.s, BS Function Supervisor, Acute Toxicology K. D. O'Malley, BS Dr. V. Pothaprayada G. C. Pecore Advanced Toxicologist Study Director Commercial Chemicals Chemist Supervisor Animal Laboratory UU01S1 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. 00018k: 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, ana tne facilities are examined by Laboratory Quality Assurance on a three month schedule. 00018a ll l< . IIh Ki:I .., l 1 . ll. l.l lII n)i 2-Mi .'.I. I-. A. Uho 1 - 220-21; 1 : 14. APPENDIX 5 K. L. iiBliiiNS - RIKEK SAEETY EVALUATION LAB - 203-1 fIfll" W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E SuDi*1'? SKIN ABSORPTION STUDIES ON FC-143, FC-95, FC-99, FC-134, FC-13S, EC-128. EC-129 and EC-98 (U U - 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 fluorochcmical 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 scrum data analysis aro 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 curtain when the remaining samples will be analyzed and their completion should not hold up your report any longor. Thank you for your patience in this matter. 7-; WCM: kill BEST co p y AVAILABLE 000184 ItIt-rM.it t.01 h ;;,|mi HitI .1 . I' I* _l-i--A.i-L.il.U-- -- "/Il /I K . A. rr<jku|j - .Hj--fu j.. n. w i u u M - z'i()-2ii 15. a p p e n d i x * i (Concluded) COMMERCIAL CHEMICALS DIVISION ANALYTICAL LAB REPORT #146 Uj f 'it jm Juoioci W. C. MCCOltMICK - 220-2E-02 V. POTHAPRACADA AND V. BUNNELLE - 236-3A HIKER SKIN ABSORPTION STUDY June 9, i960 Reference: Commercial Chemicals Division Analycical Requeue #15669 For lack of cime, only a selected set of serum sumples was analyzed. _________ TOTAL F. ppm_______ Compound FC-129 FC-134 FC--128 Females Day 1 Day 28 26.1 69.6 0.2 18.1 4.4 16.5 Males DaV 1 Day 28 11.4 23.3 18.8 23.9 1.6 ID. 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____ Day 7 . Day 14 Day 28 Dny 7 Day. .14 Day 28 1*0-143 10.1 12. i 3.5 5.4 6.8 4.0 Mi -i IhwI n l A n a I yii I M: llx y i'.itn IWimli/CC T i ' i t l m I ( . I n n i l f l l n l i - mul D. F . H a g e n , A n a l . B l o c h e m ; 8 7 , 5 4 5 , 1 9 7 8 ) . rrf.At Ml V. A. Bunnelle VAB/hc iC -/ V. PocLapragada Read and Reviews by L. D .. Winter BEST COPY AVAILABLE 000185