Document agjjYRB31Dgxnm8QL9wg0Qjb

oral Toratology Study of T-314ICoC in Rabbits RECE!VED vi Experiment No.; Conducted At: Dosing Period: Study Director: 06SITS0398 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota September 21, 198q through November 6, 1981 E. G. Gortner E. G. r-ortner Senior Research Technologist Animal Teratology Reproduction Date @E. G. Lamprecht, CVM, PbD Date Research Vete@rtnary Patholc>gist M. T. Case, DVM, PhD Manager, Pathology-ToxicoloQv' Safety Evaluation Laboratory Date summary Oral administration of distilled water solutions of T-3141COC at doses of 0, 50, 5 and 1.5 mg/kg/day to pregnant New Zealand White/Minikin rabbits during gestational days 6 through IS (period of organogenesis) was not embryotoxic and did not affect the ovaries or reproductive tract contents of the does. The compound did not cause gross, internal, or skeletal malformations of the fetuses. T-314ICoC was not teratogenic in the rabbit. T-314ICoC administration was toxic to only the 50 mg/kg/day dose group pregnant animals. The high dose does, as a group, lost significantly more weight than the 0 mg/kg/day group does. No compound-related toxic clinical signs or deaths occurred in any of the compound-treated groups. 2. Introduction a b A rangefinding studr- determined that the T-314ICoo toxic to pregnant rabbits at dose levels of 100 mg/kg/day and higher. The toxicity resulted in deaths within the first four days of dosing. The 50 mg/kg/day rabbits survived 13 days of dosing but lost a significant amount of body weight early in the dosing interval (days 6-9 gestation). The high dose level for a rabbit teratology study was set at 50 mg/kg/day based on the results of the rangefinding study. This teratology studye in rabbits was conducted to evaluate the embryotoxic and teratogenic effects of orally administered T-3l4lCoC. The study was sponsored by 3M Commercial Chemical Division, St. Paul, Minnesota and was conducted by the Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. Two sets of compound administration groups were dosed between September 21 and November 6, 1981. The protocol and list of the principal participants and supervisory personnel can be found in Appendices I and Il respectively. All portions of this study were conducted according to the Good Laboratory Practice (GLP) regulations and the Safety Evaluation Laboratory Standard Operating Procedures (see Appendix III for Quality Assurance Unit statement). The storage location for specimens, raw data and a copy of the final report is maintained in the Safety Evaluation Laboratory's record archives. Methods Sexually mature New Zealand ;ihite/Minikin female rabbits were obtained from Dutchland Laboratories, Inc., Denver, PA, and assigned cages according to a computer-generated random numbers table. The rabbits, ranging in weight from 1041 to 2813 grams, were then divided into four groups of la animals each. The rabbits were housed individually in stainless steel cages in a temperature and humidity controlled room. Food-d and water were available ad libitum. The lights were on a 12 hour light/dark cycle. Each female rabbit was injected with 1 mg of pituitary luteinizing hormone via the ear vein before insemination. The does were then artificially inseminated with 0.5 ml of pooled diluted semen. The day of insemination was designated day 0 of pregnancy. The animals were observed daily from days 3 through 29 of gestation for abnormal clinical signs. Body weights were recorded on gestational days 3, 6, 9, 12, 15, 18 and 29. The four groups were dosed with T-3l4lCoC dissolved in distilled water at 0, 50, 5 and 1.5 mg/kg/day. The solutions were administered daily using a constant dose volume of I ml/kg by oral intubation with a syringe and rubber catheter on gestational days 6 through 18. T-3l4lCoC characterization was provided by 3M Commercial Chemical Division, St. Paul, Minnesota (Appendix IV). a Riker Experiment Number 0681RB0331 @@FC-143 c Riker Experiment Number 0681TRO398 Purina Rabbit Chow, Ralston Purina Co., St. Louis, MO 3. All surviving animals were euthanatized on gestational day 29. The ovaries and uterus, including its contents, were examined immediately to determine the following: number of-corpora lutea, number of viable fetuses, number of resorption sites, fetal weights and sex, and gross fetal abnormalities. The fetuses were then placed in an incubator at 370C for a 24-hour incubation period. Following the incubation period, all fetuses were killed and examined for internal abnormalities. The fetuses were then preserved in ethyl alcohol for clearing and staining of the skeleton with alizarin red to detect skeletal abnormalities. Results and Discussion The oral administration of T-3l4lCoC to pregnant rabbits during the period of organogenesis caused maternal toxicity only in the high dose group (50 mg/kg/day). The high dose does, as a group, lost significantly more weight than the control group (0 mg/kg/day) between day 6 (the initiation of dosing) and day 9 of the study (Table 1, Appendix V). The high dose does gained weight comparable to the controls after day 9 of gestation. The mid (5 mg/kg/day) and low (1.5 mg/kg/day) dose group mean maternal body weight gains were never significantly different from the control group. The failure of the low dose does to gain body weight comparable to the control group was due to one animal (QlB2336) which consistantly lost weight during the dosing interval and eventually aborted and died. No compound-related clinical signs were unique to T-3l4lCoC treatment of pregnant rabbits. Platernal deaths occurred during the study. Five of the six deaths were terminations due to broken backs or were due to intubation error. No deaths could be attributed directly to compound-related toxicity. Reproductive function of the does and fetal survival were not affected by compound administration. The conception incidence, the incidences of abortions or does delivering early and the 24 hour incubation mortality incidence of the treated groups were not different from the control group (Table 2). T-314ICoC was not embryotoxic and did not affect the ovaries or reproductive tract contents of the does. The number of male, female, total and dead fetuses, the mean number of resorption sites, implantation sites, corpora lutea and mean fetus weights of the three compound dosed groups were not significantly different from the control group (Table 3, Appendix VI). No compound-related major gross fetal malformations were observed in any compound-dosed group. One low dose fetus had a clubbed forepaw (Table 4, Appendix VII). No internal fetal findings were observed (Table 5, Appendix T-3l4lCoC treatment did not cause compound-related fetal skeletal malformations. The incidences of 13 ribs in the high dose group and 13 ribs spurred in the mid dose group were significantly higher than in the control 4. group (Table 6, Appendix IX). The findings involving the 13th rib are naturally occurring and were not considered malformations. Findings associated with skeletal ossifiction were not different among the four treatment groups. The oral administration of T-314ICoC to pregnant rabbits was not teratogenic at the dose levels tested. 5. Table 1 Oral Teratology Study of T-3l4lCoC in Rabbits Mean Body Weight Gain or Loss (g)With Standard Deviations of Pregnant Rabbits Between Gestational Day Weighings Dose Group 0 mg/kg/day 50 mg/kg/day 5 mg/kg/day 1.5 mg/kg/day 3-6 1 J.,=: --------------------------------------------- 1.,IEmt-4 -z4 zi izI 'j -2@Significantllyower than the control (Dunnett'st test p < 0.05) Table 2 Oral Teratology Study of T-3l4lCoC in Rabbitsa Reproductive Performance and Petal Mortality Dose Group 0 mg/kg/day 50 mg/kg/day 5 mg/kg/day 1.5 mg/kg/day Total Number of Animals 18 18 18 17S Concel)tioii Incidence 15/18 83 17/18 94 11/17!1 64 9/15!@ 60 Incidence of Abortions or Premature Deliveries 4/15 27 2/17 12 0/11 0 1/9 11 a Treatment groups were not significantly different from the control group (Chi-square with One or more animals died early in study and pregnancies could not be determined one of 18 animals was terminated before the initiation of dosing because of a debilitating Dose Group 0 mg/kg/day 50 mg/kg/day 5 mg/kg/day 1.5 mg/kg/day Table 3 Oral Teratology Study of T-314ICoC in Rabbits Mean Litter Data and Fetal Weights With Standard Deviations F E. I k... F* 'Ik-ITHL. t--L. I L L:. 1.1 Ht-4 2. I. 1.,t Ht-4 L-L-. 1. 1. C.". J. 0. I A'r I (--It L:. Treatment groups were not significantly different from control group (Dunnett's t test p < 8. Table 4 Oral Teratology Study of T-314ICoC in Rabbits Number of Fetuses With Gross Findingsa Total fetuses examined Small Clubbed forepaw 0 mg/kg/ day 49 3 (6) Dose 50 mg/kg/ day Groups 5 mg/kg/ day 74 71 1 (1) 2 (3) 1.5 mg/kg/ dav 45 2 (4) 1 (2) Table 5 Oral Teratology Study of T-3l4lCoC in Rabbits Number of Fetuses With Internal Findingsb 0 mg/kg/ day Dose 50 mg/kg/ day Groups 5 mg/kg/ day Total fetuses examined 49 74 71 1.5 mg/kg/ day 45 S Treatment groups were not significantly different b (Dunnett's t test p -,0.05) No findings were observed in the fetuses examined percent of total examined from the control group 9. Table 6 Oral Teratology Study of T-3l4lCc>C in Rabbits Numbers of Fetuses With Skeletal Findings No. of fetuses examined Fontanelle not closed Holes in parietal Holes in both parietals One sternebrae missing Sternebrae not ossified Sternebrae asymmetrical Extra sternebrae Sternebrae fused 13 ribs 13 ribs spurred 13 ribs floating 0 mg/kg/ day 49 19 (30) 1 (2) 50 mg/kg/ day 74 16 (22) 1 (1) 5 mg/kg/ day 71 24 (34) 7 (14) 4 (8) 1 (2) 1 (2) 8 (16) 3 (6) 1 (2) 16 (22) 3 (4) 1 (1) 1 (1) 28 (38)A 12 (16) 1 (1) 11 (16) 5 (7) 21 (30) 18 (25)@@ 1 (1) 1.5 mg/kg/ day 45 11 (24) 1 (2) 10 (22) 5 (11) 1 (2) 9 (20) 7 (16) 1 (2) -2@Significantlyhigher than the control (Dunnett's t test p < 0.05) percent of total examined 10. TITLE: Appendix I Protocol for oral Teratology Study of T-3l4lCoC! in Rabbits (Riker Experiment Number 06SITBO398). OBJECTIVE: A teratology study will be used to evaluate the embryotaxic and teratogenic effects of orally administered T-3l4lCoC to pregnant rabbits during the period of organogenesis. The procedure complies with the general recommendations of the FDA issued in January, 1966 ("Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use"). The study will be conducted according to the 1978 Good Laboratory Practice Regulations and Safety Evaluation Laboratory's Standard Operating Procedures. SPONSOR: 3M Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: STUDY DIRECTOR: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. E. G. Gortner START OF DOSING: September, 1981. TEST SYSTEM: Seventy-two sexually mature New Zealand White/Minikin rabbits from Dutchland Laboratories, Inc., will be housed in stainless steel cages with wire mesh floors in a temperature and humidity controlled room. This strain of -rabbit will be used because historical control data is available. Purina Rabbit Chow and water will be available ad libitum. The lights will be on a 12 hour/dark cycle. TEST SYSTEM IDENTIFICATION: Each animal will be ear tagged and that number will be indicated on the outside of the cage. RANDOMIZATION: The animals will be assigned cages according to a computer-generated random numbers table. CONTROL ARTICLE: Distilled water. TEST ARTICLE: T-3l4lCoC. ANALYTICAL SPECIFICATIONS: The test article composition and purity will be determined by the Sponsor (3M Commercial Chemical group) prior to the start of the study and at the end of dosing. The sponsor is responsible for retaining a reference sample of the test and control article, as required, for GLP compliance. FC-143 DOSAGE LEVELS AND EXPERIMENT DESIGN: The test article will be dissolved in distilled water daily. The test article solution and control article will be administered by oral intubation to the rabbits on days 6 through 18 of gestation according to the following: Dose Level 50 mg/kg/day 5 mg/kg/day 1.5 mg/kg/day 0 mg/kg/day Group Size is 18 18 is The oral route of administration will be used because toxicity has been defined by this route in a rangefinder study. No dietary contaminants are known to interfere with the test article. On the day of breeding, each female will be given an intravenous injection of 1 mg of pituitary luteinizing hormone to induce ovulation. The does will then be artificially inseminated with 0.5 ml of pooled diluted semen collected from New Zealand White/Minikin male rabbits. The animals will be observed daily from day 3 through day 29 of gestation for abnormal clinical signs. Body weights will be recorded on days 3, 6, 9, 12, 15, 18 and 29 of pregnancy and the rabbits dosed accordingly using a constant dose volume of 1 ml/kg of body weight. The females will be killed on day 29 and the ovaries, uterus and its contents will be examined to determine: number of corpora lutea, number of fetuses (live and dead), number of resorption sites, number of implantation sites, pup weight and gross abnormalities. The pups will be placed in an incubator at 370 C for a 24 hour survival check, The following day the pups will be terminated and their viscera examined for any internal abnormalities. The pups will then be fixed in ethyl alcohol for subsequent skeletal examination after clearing and staining with alizarin red. SAMPLES FOR POSSIBLE SPONSOR COMPOUND LEVEL ANALYSIS: A blood sample will be taken pre-dose, on day 18 and on day 29 of gestation from the same six rabbits at each dose level. A liver sample will be taken from the same rabbits on day 29 of gestation. The samples will be labeled, frozen and transferred to the sponsor. 12. These samples are not considered an integral part of the teratology evaluation of T-314ICoC in rabbits, that is they are not per se a part of the teratology study. They were taken at the sponsor's request because they may supply useful supplemental information. The samples will not necessarily be analyzed; the extent to which they are analyzed is a matter of scientific judgement by the sponsor. The results of these analyses, if and when they are completed, will be reported in a separate report. A copy of such report will be sent to the study director for inclusion in the Safety Evaluation Laboratory record archive file. Alternatively, the sponsor can notify Safety Evaluation that the samples will not be analyzed. DATA ANALYSIS AND FINAL REPORT: The proposed statistical methods to be used for analysis of the data are: Dunnett's t test for dam and pup weights, number of fetuses, number of resporption sites, number of implantation sites and number of corpora lutea; Chi square for percent abnormalities. The proposed date for the final report is 2-3 months after detailed pup examinations have been completed (approximately first quarter, 1982). 13. Appendix II List of Principal Participating Personnel NAME FUNCTION Edwin G. Gortner Elden G. Lamprecht Gary C. Pecore Venkateswa Pothapragada Larry Winter Loren 0. Wiseth Study Director Veterinary Pathologist Supervisor - Animal Care Commercial Chemical - Analytical Commercial Chemical - Analytical Technician APPENDIX III 14. STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: 0681TBO398 TITLE: Oral Teratology Study of T 3141 CoC in Rabbits Audits and/or inspections were performed by the Riker Compliance Audit unit for the above titled study, and reported to the study director and to management as follows: Date Performed Date Reported 14 October 1981 15 October 1981 19 October 1981 3 November 1981 6 November 1981 17 November 1981 12 January 1982 18 February 1982 16 October 1981 21 October 1981 27 October 1981 11 November 1981 11 November 1981 1 December 1981 27 January 1982 19 February 1982 C:@oo'mmlpa"lance-Tu-&.it' Riker Laboratories, Inc. 2- I)taef 15. Appendix IV Oral Teratology Study of T-3l4lCoC in Rabbits Test and Control Article Analytical Results T-3l4lCoC Commercial Chemical Analytical Report #308 GLC of Methyl Esters C6 Acid C7 Acid CeAcid (all isomers) Cg Acid CloAcid cx Acid Prestudy 0.2 0.6 97.6 .8 .2 .5 Poststudy .2 .4 98.4 .4 .2 .4 All values within experimental and integration parameters. Element F c N H 0 by diff. F- MW = 431 Theo. 66.13 22.27 3.24 0.92 7.42 0 Elemental Analysis Prestudy 66.2 22.2 3.5 0.7 7.4 68 ppm Poststudy 65.9 22.2 3.6 0.7 7.6 68 ppm Spectroscopic Infrared spectra #16474-1 and 17958-1 are identical and match reference spectra. NMR spectra H 8386, F 8388-9 (Pre) and F 10163-4 (Post) are identical and match reference spectra. The chain is 79% straight chain, 9% (CF3)2CF- branching and 12% back bone branched. Conclusions T-3l4lCoC has an analysis within specifications, is stable and is representative of commercial material. Poststudy Control Article Commercial Chemical Analytical Report #294 Control Article Distilled water Theoretical mg/ml T-3l4lCoC 0.0 Actual mg/ml T-3l4lCoC 0.0 T T T P-='T:, @TPT t;:*,:-iC-1'17T,,74T +,_',:T oci7i-7@T T t,!;,;T T T,z,;T T t-4 '3Tt4 T, Cof-iT7 '71c 17, T:7f-17 =I 17.7 IDTT@ r@TicT T i..n.--'.-...7 7:= 7 171:7 T -, T:::f: tz T,- "T- 1.71 C4 t7 I T @-':-'T7 T.- 17; 7 -L7, -Z i7l-- @7.T -7i7i L7! T T:= T t7l..' T@7 -,74 7' T7'@@ T Z 7- TT-7' T Ci+.-!-@T T T 1--T.:"r I'--. c-I7@' E- T #F.!;@F!T ,: T T -7 T T j- ::T4 @T'@T PC-,7@T C@-I'=iT T T T '-C-74T T, T T T"@ T ozC, T T 17i:T ':-4 T 7@ 7- T 1;7@t,:'T -'T t-C-i T --'4T T T ::qT. T @-.1 T @.4 -ETt-4 T!' -------------------------------------------------- tF-t- :@@T !;T T E. 74 :7* sTvmTW qtmubead zo; suoTlrTAOa PzvPtre4g Ptre s4tt6T9M APOS tre9W tr4TM (f))sltlbTOMAPOS TvnpTATPuI sltqqird uT 0001VIE-X ;0 APn4s AbOT04v'al TRIO A x-rpuedctv '9T 20229 UOT4Pqn4UT POTP TM-FUV @@4 f T i @4 -7-r'7 -TI-17, i-@i.:171 7 171 .7' L7t 171 7- T'@ C':@ T T 17@:-T, t, T1 T. -- =, C, T ;7 @7 7 @7 I-T, C.-T., T i-7i,m f-T- 1717.@ TT,- T t7.-'z' 7.1 7. ', 7. -17 k@T 7' =oI @71, I T -71171 'r T 7 r7.1=:'@7' 17i t i, .77 t@-..'T =iT T T T t- '74-1 !;;T:=.,CTl,:,IT f- T T t -74T Tc T i,! -.@T T T@ @l- -:IT t-l-T, T T7 T,::Ti T. T T i7im4::T: :'T,-,- IT @F -,=,T T:=,-=,t.- i@4 T i-, TI 77 -------------------------------------------------- ,F7- -'T T ;7T '74 sTL'ul-ruv4UeUBO.Zd .10_ZSUOTqle-rAsa pavpuie-4g ptre sqiq5Tat4 APOS ue9W tr4TI4(5) S'4lqBT9tAiPOIR TvnPTArpui SlTqqL"d Ut DODIVTE-L ;0 Apnis ABOT04VZBI TRIO (panu,r:Zuo:)A) XTpuaddV 'LT zoaaa uoTqpqn4uT petp Tleul-ruV T 7T 7z' T- -74 Cit7,T T Ti T - .1-'T C'7,@'T T _:'7 1 .7-=Ti 171 171 171 T:=@- T T T 74 @7.'@' T i7f T tz,:4I,' 7 -T T CiP;T7 171 T 74, 17' T T T @'t, 4;1 7 1- 4., 41.T.t1.4L. ::3T ::1 T -4 ',7. 7 ::7: 7.,',771. 1,i.L-i I T 77 T T T t-7@7:@ -7:--:@ t7i -Z,-7-- -T TT 7- j. -F7 L i-I L7,'f=-'':7 t.771 -E.,- T T tL7. T 74 T T L7,. T,' 74. T. T T T 74 T 17 @;Tp-zT T 7 z t.,'747-*.7 T TT i T;=,:@7- -------------------------------------------------- T T T e. .@7 s'Erm'ruv 4treuBoad aoj suo-r:Z,,-rAapazvptm-4S pue S'4tiBram Apog uv;aw q4TM (5) s-4lqbT8t4APOS TLnpTA-rpUj S4Tqq'LI'dUT OOOTVTE-L ;o Apn4s ABOT04vzaL Ivao (POnuTluOD) A xTpusddV 'ST Xovq uexoaq - paTITX lvmTuV tppap aaogaq saep xnog pa:"oqe - p8Tp TVMTtiv ie I Ft ri @-t C'l Cl C-1 171 T "i-i@::',!T:@@,@T -171 q, T 7-,..-:-:I"Ir ci q i7l T :-T i -T T t7ir. TL- T T T. 'T T T-- i7l ci Cl -171 q t-- T: l@11-1,T C"IT@ T .'T T C@:-T, 17i' T lyt@.'T '74T T -:4T L71 T -C:t1 i 1'7 :7@Ti,-, 7 t7i -7@ -t7 L7, T,--.!7.1. Ci.. .- - .-.Z T-7.. . t . I- 171 L72,7@ T t, 7:' T i7t4, t.:J.:, 'T;=.7' '@T T 171 -":7 T 7*:-@T T -:T'-@ Ct- iT T @-FT,: T,:::--- 7" i- L7 @@.7 17, :::!,71 TT@@ --T T T T@--t7l7' T T -74T 7 T t7C,, t7i '!:.7- -:1 c 'T ---------------------------------------------------- T st,ew-ruy-4upube-iczio; suo-rqvTA;aapaeptre:zsptre s,4iqB-Fef4 APOS uei)W tRT14 (J5s)4l4bT9t4APOS TenPTAT.PUj s4Tqqe*d UT :)OOTVIE-,L90 ApniS A6OTO4t'a9.LT'e'O (papnTOU00) A xTpusddV *6T 20. Appendix VI Oral Teratology Study of T-3l4lCoC in Rabbits Individual Litter Data With Mean Fetus Weights 0 mg/kg/day t@tI-I1-;FIL VIP-IE.LE FETi-l'-::ES E.-EFIL.', P'E.E.CiF.I,!-IF,LFit-4 ill F Tf--IT'RLFETI-ISE---, -IHIIC't-4LI-IFER F 1 1*E r i.@ cl.. .4 '47'. 44. E..4. cl. ci t7i C L Delivered Early ci Li 7- -@;4. -:4 21. Appendix VI (Continued) Oral Teratology Study of T-314ICoC in Rabbits Individual Litter Data With Mean Fetus weights 50 mg/kg/day F-IHL '.'IFiE,'LE ;If iz TC,TAL FETI-1--@E-: F,TlLli-,'iFirii--IrL-l4-.,-TEH I-IEFitF-E4T.I-I*-:WT:,.@''.I--3.A Fl'-,-i-i ti F ci 7 5 -IF ci r -IF E 1:@t4 r-4-f t@. e4 'Li.4 l 22. Appendix Vi (Continued) Oral Teratology Study of T-3l4lCoC in Rabbits Individual Litter Data With Mean retus Weights 5 mg/kg/day FE'rL[---E---.C.-EFi[@ f-i F TCI-i'FILFETLI'-=ES F,T'lCft-TJRTIC't-4 LIJTEFI I T E'-='. I-ILFIN F E T U t-1 I-TJ --.'13 F k:l F ci f--..Ll C-1. r ci ..E,.c 5 .-4Cl. I ..I@-i. 7 1-1 C 7. C. E. -i4. 23. Appendix VI (Concluded) Oral Teratology Study of T-3l4lCoC in Rabbits Individual Litter Data With Mean Fetus Weights i.5 mg/kg/day ritI-itIFiL VIRE:LE FETUSES C@EFIC, t-1 F TCITF-ILFETUSES F.,E:F.C,IFt,-lF,LRt4CCIF'.PFR t-lERt-F4ETUS F,TICt.4 THTICi?-4 LLI'REFI Ft'-.."3 t-I '7,ITE'z SITE'-Z I-JT('G", F T-JOT F,F,Ei:it.4HNT .'75-, 1-4CiT PF*Ei3t-48t-4T t.4CiT F-'F'EC3t.4F-lt-4T !E@ 5 0 [:,ERL., E. "-Z'51 tiCiT PF.Ei3t4FiliT 5 T-JOT PF,Ei:it-4Rt.4T 7 i 41 5 4 E., C, 7 ci 5 .E: 2 @:L tF .E; 4 54 E-EFILHE-OF:TE[i 0 C-1 5 - c-IC1. 1 4 Cl. 1 4 Cl. IC,. 5. 7 21-1*@. :L Dose Group - 0 mg/kg/day Dam No. Total fetuses examined Small Dose Group - 50 mg/kg/day Dam No. Total fetuses examined Small Dose Group - 5 mg/kg/day Dam No. Total fetuses examined Small Dose Group - 1.5 mg/kg/day Dam No. Total fetuses examined Small Clubbed forepaw Appendix Vil Oral Teratology Study of T-314ICoC in Rabbits Number of Fetuses by Dam With Gross Findings 2321 2322 2323 2324 2338 2339 2686 2703 2704 2717 27 5 3 7 1 7 1 7 1 6 5 2 1 2325 2326 2328 2341 2342 2643 2644 2689 2690 2691 26 5 6 7 6 4 5 1 3 a 5 I 2329 2330 2331 2332 2693 2695 2709 2710 2711 2712 27 8 2 8 7 7 6 3 7 7 9 1 1 2697 6 2698 5 I 2699 6 2700 5 2714 7 2 2715 7 2716 9 Dose Group - 0 mg/kg/day Dam No. Total fetuses examined Appendix VIII oral Teratology Study of T-3l4lCoC in Rabbits Number of Fetuses by Dam With Internal Findings 2321 2322 2323 2324 2338 2339 2686 2703 2704 2717 271 5 3 7 1 7 1 7 1 6 5 6 Dose Group - 50 mg/kg/day Dam No. Total fetuses examined 2325 2326 2328 2341 2342 2343 2344 2689 2690 2691 269 5 6 7 6 4 5 1 3 a 5 9 Dose Group - 5 mg/kg/day Dam No. Total fetuses examined 2329 2330 2331 2332 2693 2695 2709 2710 2711 2712 272 8 2 8 7 7 6 3 7 7 9 7 Dose Group - 1.5 mg/kg/day Dam No. Total fetuses examined 2697 6 2698 5 2699 6 2700 2714 7 2715 7 2716 9 Dose Group - 0 mg/kg/day Dam No. Number of fetuses examined Fontanelle not closed Holes in the parietal Sternebrae not ossified sternebrae asymmetrical Extra sternebrae Sternebrae fused 13 ribs 13 ribs spurred 13 ribs floating @.)iai ietalulogy Study of T-3l4lCoC in Rabbits Number of Fetuses by Dam With Skeletal Findings 2321 5 1 1 1 2322 3 2 1 2323 7 4 1 1 1 1 1 2324 1 1 2338 7 4 2 1 2339 1 1 2686 7 4 1 1 1 2703 1 1 2704 6 3 I 1 2717 5 1 2 1 271 6 1 2 1 Dose Group - 50 mg/kg/day Dam No. Number of fetuses examined Fontanelle not closed Holes in the parietal Sternebrae not ossified Sternebrae asymmetrical Extra sternebrae Sternebrae fused 13 rix)s 13 ribs spurred 2325 2326 2328 2341 2342 2343 2344 2689 2690 2691 26 5 6 7 6 4 5 1 3 6 5 2 2 3 2 1 I 1 3 0 3 I 1 1 1 4 3 7 3 3 1 2 2 1 1 1 5 1 3 1 2 2 Dose Group - 5 mg/kg/day Dam No. Number of fetuses examined Pontanelle not closed Sternebrae not ossifieti Sternebrae asymmetrical One sternebrae missing 13 ribs 13 ribs spurred 13 ribs floating Oral Teratology Study of T-314ICoC in Rabbits Number of Fetuses by Dam With Skeletal Findings 2329 2330 2331 2332 2693 2695 2709 2710 2711 271 a 2 8 7 7 6 3 7 7 9 2 1 5 2 3 1 1 1 2 5 1 3 1 3 1 2 1 3 1 1 7 1 3 3 1 3 1 3 3 1 1 3 2 2 2 1 Dose Group - 1.5 mg/kg/day Dam No. Number of fetuses examined Fontanelle not closed Holes in both parietals Sternebrae not ossifipd Sternebrae asymmetrical Extra sternebrae 13 ribs 13 ribs spurred 13 ribs floating 2697 6 1 2698 5 2 2 2699 6 3 2 1 2 1 2700 5 1 1 1 1 1 2 2714 7 2 3 1 1 2815 7 1 2 3 2 2716 9 2 1 3 2 1 DISMI&RJTION LIST 14. T. Case E. G. Gortner (Oiriginal + 1) r-. Keller (QA Filel E. G. I4jnprecht E. L. Mmtsch -+-A. A. Nelson - R. E. Ober U. C. 14cCormick F. D. Ciiffith (2) U. Ei. Pearlson G- R. St:ef feim T. D. Henderson -* X. L. Ebbens