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/q (U 0 6 -0 4 & 5 RECEIVED Oral Teratology Study of T-3141CoC in Rabbits iYVir\r\ I S' ^ WUw'U Experiment No. : Conducted At: Dosing Period: Study Director: 0681TBG398 Safety Evaluation laboratory Riker laboratories, Inc. St. Paul Minnesota September 21 1984 through November 6 1981 E. G. Gortner E. G. Gortner Date Senior Research Technologist Animal Teratology Reproduction E. G. Lamprecht, DVM, PhD Date Research Veterinary Pathologist T6 ^ . e/tVtz M. T. Case, DVM, PhD Date Manager, Pathology-Toxicoloov Safety Evaluation Laboratory 003052 1. 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 18 (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-3141CoC was not teratogenic in the rabbit. T-3l41CoC 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. 003083 2. Introduction ab A rangefinding study-- determined that the T-3141CoO- was very 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 study in rabbits was conducted to evaluate the embryotoxic and teratogenic effects of orally administered T-3141CoC. 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 II 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 White/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 of18 animals each. The rabbits were housed individually in stainless steel cages in a temperature and humidity controlled room. Foodil and water were availableadlibitum. 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-3141CoC 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 1 ml/kg by oral intubation with a syringe and rubber catheter on gestational days 6 through 18. T-3141CoC characterization was provided by 3M Commercial Chemical Division, St. Paul, Minnesota (Appendix IV). Riker Experiment Number 0681RB0331 FC-143 Riker Experiment Number 0681TR0398 Purina Rabbit Chow, Ralston Purina Co., St. Louis, MO 003034 |D.|o |cr|(u 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 37C 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-3141CoC 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 (Q1B2336) which consistantly lost weight during the dosing interval and eventually aborted and died. No compound-related clinical signs were unique to T-3141CoC treatment of pregnant rabbits. Maternal 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-3141CoC 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 VIII). T-3141CoC 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 003035 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-3141CoC to pregnant rabbits was not teratogenic at the dose levels tested. 003086 Table 1 Oral Teratology Study of T-3141CoC 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 m g/kg/day 5 mg/kg/day 1 .5 mg/kg/day l 'RV 3-6 8 1 2 1 2 18 28 I'IEmN -i3- - 5 IS 2 8 48 102 S i i~lN. L 't V 5:i_. s 2S. 2 2s. s 2 o . -i 2 8 . 2 1 2 ? . 8 i-iti-iN -2 - 8 2 . 2 1 i *2* C_'_! J-t't' -"I riiv. L 't V t y . y * 22. u 56. 4 50. *33. & rih n N .'1 1 6 8 8 *+4 1 Hr-.:. L 'E V j-8. 1 4 . 2 8 2 . 1 r'8. 1 0 1 . o 4 ci -I i'ttc. i-if-4 10 --I - 1 '.V i Hhi. L C. V !_L. 1H. 1 ,''8. 8 k} r^ij- *2- a -- Significantly lower than the control (Dunnett's t test p <0.05) G030S7 Table 2 Oral Teratology Study of T-3141CoC in Rabbits Reproductive Performance and Fetal 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 17- Conception Incidence % 15/18 83 17/18 94 11/17- 64 9/15- 60 Incidence of Abortions or Premature Deliveries % 4/15 27 2/17 12 0/11 0 1/9 11 24 Hour Incubation Mortality Incidence % 0/49 0 1/74 1 0/71 0 1/45 2 a Treatment groups were not significantly different from the control group (Chi-square with Yates correction p < 0.05) -- 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 condition G03088 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-3141CoC in Rabbits Mean Litter Data and Fetal Weights With Standard Deviations-- HO. OF V IA B L E HE. 1U S E S mH I lifiL S li F TOTAL 11 STAN L'tV y 1. _L t> 1. i 4. 0 2. 0 1.4 STAN L'tV cL. i 1. 6 1. 2- -> 11 STAN L'tV SIAN L'tV j . . r' 1. 7 i . 4 3-. E *3 1. 0 i . 6. 5 2. 1 if.. '* 1. 4 l't: I II * REbURF' 1I UN IM PLA N TA TIO N t o r p o r e HLHN 11 F t 1U SES su es S l I ES LUTEA FETU Sto : 0 0 0. 7 0. 0 1. 0 J. c.. 2. 1 t*. 3! 1. 5 4.... 4 i 6 0. 1 0. S o. 0 U. 0 0. 0 0. 0. 4 0. S 5. 3 2. 4 0. 8 0 6. 0 2. 1 1' . c'.* 41. 2 *.... u 3 b. b 0. 0 11. H ti. t. 0. y M 1. 6 7. 9 ...... 'I i : ' 4'i .2. J BEST COPY AVAIlABLE - G03089 -- Treatment groups were not significantly different from control group (Dunnett's t test p <0.05) Table 4 Oral Teratology Study of T-3141CoC in Rabbits Number of Fetuses With Gross Findings* 8. Total fetuses examined Small Clubbed forepaw 0 mg/kg/ day 49 3 (6 ) Dose Groups 50 mg/kg/ 5 mg/kg/ day day 74 71 1 (1) 2 (3) 1 .5 mg/kg/ day 45 2 (4) 1 (2 ) Total fetuses examined Table 5 >logy Study of T-3141COC in Rabbits : Fetuses With Internal Findings^. 0 mg/kg/ day Dose Groups !50 mg/kg/ 5 mg/kg/ day day 49 74 71 1 .5 mg/kg/ day 45 a -- Treatment groups were not significantly different from the control group k (Dunnett's t test p < 0.05) -- No findings were observed in the fetuses examined ( ) = percent of total examined 003090 9. Table 6 Oral Teratology Study of T-3141CoC 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 Stemebrae not ossified Sternebrae asymmetrical Extra stemebrae 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) S (16) 3 (6 ) 1 (2 ) 16 (22) 3 (4) 1 (1) 1 (1 ) 28 (38)-- 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 ) a -- Significantly higher than the control (Dunnett's t test p <0.05) ( ) = percent of total examined C03091 10. TITLE: Appendix 1 Protocol for Oral Teratology Study of T-3141CoC-- in Rabbits (Riker Experiment Number 0681TB0398). OBJECTIVE: A teratology study will be used to evaluate the embryotoxic and teratogenic effects of orally administered T-3141CoC 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: Safety Evaluation Laboratory, Riker Laboratories, Inc. , St. Paul, Minnesota. STUDY DIRECTOR: 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-3141CoC. 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 003092 11. 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 Group Size 50 mg/kg/day 5 mg/kg/day 1.5 mg/kg/day 0 mg/kg/day 18 18 18 18 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 37 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. 003093 12 These samples are not considered an integral part of the teratology evaluation of T-3141CoC 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). Appendix II List of Principal Participating Personnel 13 NAME FUNCTION Edwin G. Gortner Eiden 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 003095 APPENDIX I H STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: 0681TB0398_____________________ _ TITLE: 0ral Teratology Study of T 3141 CoC in Rabbits Audits and/oT 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 b 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 14. Compliance Audit Riker Laboratories, Inc. G03096 15. Appendix IV Oral Teratology Study of T-314lCoC in Rabbits Test and Control Article Analytical Results T-3141CoC Commercial Chemical Analytical Report #308 GLC of Methyl Esters Cg Acid C7 Acid CgAcid (all isomers) Cg Acid C-jgAcid 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 Elemental Analysis Element F C N H 0 by diff. F- Theo. 6 6 .13 22.27 3.24 0.92 7.42 0 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 MW = 431 Spectroscopic Infrared spectra #16474-1 and 17958-1 are identical and natch 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% ( C F g ^ C F - branching and 12% back bone branched. Conclusions T-3141CoC has an analysis within specifications, is stable and is representative of commercial material. Poststudy Control Article Commercial Chemical Analytical Report #294 Control Article Theoretical mg/ml T-3141CoC Actual mg/ml T-3141CoC Distilled water 0.0 0.0 C03097 BEST COPV AVAIIABLE Appendix V Oral Teratology Study of T-3141CoC in Rabbits Individual Body Weights(g) With Mean Body Weights and Standard Deviations for Pregnant Animals DH't1 2 6 0 12 15 18 0 MG/KG/DHV nib NIB NIB NB NIB NIB: NJ_6 NiB NIB K*:LB NIB N _lB NIB NIB NIB 20 2 1 lo? 0 1607 1632 1704 1702 1040 567 0JlZcZ IS62 1005 1005 10 00 1060 204 7 2107 X--XJ- 2150 2.LOS 2 2 2 1 X2 '1 2200 2246 2542 22 24 JL 3X X6 3 1620 1602 686 1754 1802 c-J-J-r 1675 1678 j.500 1612 674 1718 1 0 2 2 cZ----O 1722 1760 170? 1:050 1042 2623 2 2 2 0 ^ j.^ 1715 17 So 1 r*33 1 :0'+0 1050 10 0 2 2 1 1 2 Xtz>c*6 2x63 xj t7 2 2 2 1 2214 2422 24 72 .7_1t'X X .JiX 2251 2 J-'4iZ. 2 26 0 2 Jo 7 24 50 .2 ,'0i 2 2 'i7 2262 XX6 3 2262 2204 2214 2 1 0 X i'2*X 2445 2400 2400. 2 J--> loir* jN.jl.1 2260 7'07 2106 0106 2107 217 5 XXJ-J- 2 2 r' 2424 2.04 262'3 2126 2146 2i40 2200 ?. 5ci 240:1 __7X ' XJ-J`! ,7;--7X 222 0 2X; 2 ^x6 2J2 2508 2i6 io50 1010 10:25 1040 1 0 76 1 0 1 0 2 1 1 0 HERN 3x2 2036 2 0 2 1 2*330 2 10 0 2140 2251 xT HN. L'Ev2 iX*'}.XXX *Z'. i'z04. 22 04. 02 --. i'"izZ74. 42 25. 0 NON PREGNANT ANIMALS NIB 2140 1564 15 77 1550 1551 1525 1554 1500 NIB 26.'05 1020 1760 154 7 1062 20:34 2120 247:0 NIB 260:7 15010 x i4 160*0 1580 1618 1001 1721 003098 BEST COPY AVAII ABLE Appendix V (Continued) Oral Teratology Study of T-3141CoC in Rabbits Individual Body Weights(g) With Mean Body Weights and Standard Deviations for Pregnant Animals L'ftV It! IS o0 MG KG,DHV 01B DIB DIE: DB OxB DxB DxB DIB ij k D1.B >2i.B ij iB J Zr.ix Oii:' DIB ijx B 22 X "!1 X X J-'X 2 x 4 8 2 1 2 2 2 4 2 2 0 8 4 2 2 x 4 2 4 S 4 2_ Xo 1 6 S It1313 1 6 5 8 1 7 0 5 X lb"3 1 7 4 8 2 0 X 4 22 lx 74 x 7 2 2 16' (4 17 27 1 7 6 0 1 8 1 5 I S O S __ _ S .X 0 2 2 1 7 2 1 7 5 2157' 2 2 4 * 2 x 4 4 2 4 8 8 22 HX 1 3 6 0 IS 4-0 loll-' 1 7 8 5 1 S 22- 1 8 8 7 2 1 2 4 4. X 13 38 l.lX i' 1 r'G 'i IS SI 1 8 0 8 x S x 4 2 1 x 4 22 J ix'71 1 6 1 1 x I'!j 1 6 x 6 1 6 11''i' x 724 x 8 6 5 .JJ ll -JJ 00 X,_.10 J_; 00 -2.-2-'7 X J c'3 Xl' t`i' _ "X X-._X xx4 _ X Jijx' X X rIJC' X,'I8 18 00 2:6 -tJ 2 D -i6 2x4 5 *1X X 0 X 1 O 2 _ 11J Xl-00 Xll-l i- 201 2- J0 8 JT1 1.0 c`8 X 0 dJ 2 1 SS j. -- (}H 217 4 2 .1 1 ? 2 0 !7 2 1 0 2 u2i''J -1 -- '!!J- -- -11_] Jj'-i 1 -,cj:|--' , ,'nk .f\ '4 -i 1 ... 7 10 2814- XJI,J>''{ 20 O 1 X --1j'l'i I X " X 0 o 8 X x4l Xl'Xx X X o 0 X 1'+0 XO01 x801 . i*H -.1r'ix 14-a ij . C: 10 0 k 1 ...-'6 l x * 7 X O Jj'! 1 8 x 0 2 i.Sx 2 ,". .- i:-' 2 - 227 x X X X X 22 20 15 lx M E A N __{Jj J.. .20 68 XX 22 2 D 2 "i 2 0.-?4 2 1 4 7 2 7 lx 1-fHr ~ Z. J xx. 8 x Jr'. MX 4h. VJJ.X X . b _!xS. 0412. 5 NuN FPEGOfiNT rNIrlnLS CHS 2, i 3 _ 1 5 x 2 2 2 7 2 X j 8 >1, 2142 204X 2226 a Animal died intubation error 003099 BEST COPY AVAI1ABLE18. Appendix V (Continued) Oral Teratology Study of T-3141CoC in Rabbits Individual Body Weights(g) With Mean Body Weights and Standard Deviations for Pregnant Animals DrtV 2 x 9 12 5 I S b rlu,- Kb,- 'DHt F IB -.Lb F x = r.LD r ib r ' i c: r ib - j x r ib '* -i-b r ib 2280 2221 3 - 2-2. 2x822x3 b .i i 1 J. 12 , '__ L ill1i" P XXx 1521 1588 1582 :L*z- r' .1 1 8 8 0 1 6 8 b ".* ---j`i 2-120 _ 2 l x x x T 2 , '>b c* 2 8 4 1 2 6 5 x 2 OB V7 2 x 2 2 1 0 7 5 1 8 8 8 1747-' 2'i l 2 2i ! i 2 2 7 0 ci i> 2 i- u 2 1880. 20 28 2 12 b ii-_ bb 2 4 2 8 24 2 7 21:57 2 2 8 1 2 2 4 0 1848 1712 i 778 1745 1802 184 b 1-1'--4`"T ''"i 2 54 X 2 `r*04 2 '2 B ' ^i 212b 2108 iiH 1 7 8 2 1 8 2 5 1 8 75 22..: 2> 2 2 8 4 2 ! 4 2 i_: _L r 22X7 2 2 0 1 2 2 ,- 0 >J.0 0 2 4 1 8 2 4 2 8 2 4 18 o0 1815 1J 8 * 2 784 r 24001 *-10 t``li c *2' *7' 24X0 1520 j h ^V, ribfif ) 2 1 0 8 2 1 5 8 J Jit`2 2 1 8 8 2 2 2 5 2-1-68 ' r-1 Lt v . ,8. 22 6. 52 C'wl. --5 4 . 8 2 2 4 . 22 i S . 0G 2 4 . 4 N L 'N P k E 'jN h N 'i rtN I I-'ImL S r 2.5 P ib rb r'lib r ib r _LB -12 4 XI i 44-2 22 48 1 8 x 2 2 4 i' x 2 8 0 2248 1842 2804 2607 * "4P"i 18501 1 I' 1 8 0 4 1882 1015 10x0 2 x 2 8 2 x 4 - 2 2 4 7 2 1 0 2 8 i 7 20 18?' 3 2 0i 5 8 2 1 2 0 2 2 2 4 2642 0i -- 0 1717 X005 1710 1028 18x2 1844 1884 2061 1887 22x2 1720 1822- 2 0 1 8 -ilOPt 2 x 0 1 c ; 4B* 1 0 8 0 ^ JL?" ? 2 2 8 1 .-**4o Z' 01 `J 1772 873 1874 i-1 5 -- Animal died - intubation error 003100 Appendix V (Concluded) Oral Teratology Study of T-3141CoC in Rabbits Individual Body Weights(g) with Mean Body Weights and Standard Deviations for Pregnant Animals 1 1 1 I V1 CO L'hV 1 *z> 12 15 `2 i . 5 i'i>_J7.0/ L'M *_!.2 .t j 01b 4 -Lib i1: Lb ib L !J_ '/.Lb l- ib 1 /. In 40 2 7Uy i .i __ ; 1 - . i x _i0i'''2- 2 1 7 ? i c b a 19'18 b llO 2211 .~'b ,210 1 _Lc-J-1-' 1 o `4o .. .: 7"13 u_1i -{-- 2 j X, 0 x ,_5 2 b y X99 7 _b 8 x 1952 220 S 2x51 1674 2 10 r 2"ilX2b.jL0 19 7x 1881 x. 18 1 9 9 5 2 tj 8 0 2220 2x17 2281 2454 1892 1782 X ' 1Cl0 2 9 8 2 4 ' I X- 2 4 2 2 2 b 4 if* v>b i b lb " 10 Ix^Do 1828 t.ii --a 2122 240x 2 2-i_!Zj 2 4 5 1 2 b 0 7` 2 8 2 9 1829 04 7 *`t- ?. ' ..it- l b 2 4 7X- 2 j- r2*' i 2 b 0 x-0 ! x* 1912 20 b l _j.8 x 2x89 2204 2201 22x0 j_. `^1 2 0 x 7 - f nr !. L'c v . 01 2 b . <2 'L 5 / . I . 1i t . 4x 8 7. 9.1: 4 1 . 8 ilGN bbx'xN H N T R N lW riLS 2 -i 2-2- 2 2* -/ 2 1 ('1.4 2 214 2 X-0 5 2 x 5 4 2 2 r 2- 2 x 5 4 l b i! I 1 1 b 0 0 X 0 9 1 18 8 0 1, 44 1 7 4 0 1 8 0 9 18 71 1H-, x .j 19 1 , 1 4 2 1 2 9 2 1 9 8 22 > 5 22-21' 2 2' 21 2-2' ' x b 2 J 7'i:i 1 45 4 1 4 9 4 0- 0 0 0 01 2.b cl'J 51 l b ! -1 1 C l 8 1 8 1 9 x 8 8 7 1 9 4 ? 1 9 9 5 2 0 5 7 x b - - ,2 i u4 1 14 0 ' j^l' i9 7 x X'8 l o 2 5 170X 1 8 74 i t 2 > 1 J- 2 xxi 4 y - 0 b 0 0 0 0 lb ' 2 ' 2 b 1 9 5 2 1 9 8 2 0- 0 0 0 0 Animal died - aborted four days before death Animal killed - broken back Itrip 003101 0 mg/kg/day Appendix VI Oral Teratology Study of T-3141CoC in Rabbits Individual Litter Data With Mean Fetus Weights 20 hnihhl VIABLE FETUSES DEAD i-1 F TOTFtL F E T U S E S R E S U R Ii'!PLAN C 0 ftPftft M EAN F-ETUS WT P T 1 0N T H T 10 N L U TE ft AVG M F SICES SITES !j.E 2 2 2 1 iB 2 S 22 a b .XX-ciX<18 2 2 4 XX 2i l4 -2 X0 - i 1 'X C* ixb ;J.b `.LlT;X b .i_u; J..b L. J- Z* ic It. J_b 2_ ,, X Ci'u ,Xb C`*Z` Jt':- ) 26*8 2 r'Si 'Yj_;* ;*1 2 U4 l.1rX i X rX 'Z' ,i u1 1 NO i PftE>2N A N i N O : pp.b ":!!ANT 2X i'! Pft:tijNANT' O b ?_s"*j L1 AtN .'ft!ItL1 Delivered Early X 'J X ib 4i -2 b y 0 u 0 0 0 111 0 0 0 0 ib 0X y7 i2 0r 1X 0 X. 4 2 8 42 0 43. 2 8 '1X X- 41. X- 44. 2 r' x-|- 2 Q 4- x-b. b 4 54 u 04. 0. 0 *X C; !< -1 Z11*. X- 0. ill rr--. b 04 24 0 X--X1. 'z* X '4 0 f-, 0u ,x z* 0 0.1. b 01. o' 0. 0 b 3 18. Q 41. 3 -- " 2 7;-; *ri >Z` 2 8. r 2 b. 4 2 S . 3 HSTCOPYAVAIIMLE 003102 50 m g A g / d a y b est co p ya v a iim le Appendix VI (Continued) Oral Teratology Study of T-3141COC in Rabbits Individual Litter Data With Mean Fetus Weights 21 H N IHAL v I R B LE F E T U S E S DEAD 1 F T O TFlL F E T U S -LuT' 4 - 2 0 J_lT1 --- -O --U jlh: ^j o lB ~ . i~` ' . i j. - 4to 3 SSS1 - 4 t :.- lJ & 3i0 --' !** --3 - h BOF: TED 34 -- - lJ U1 12 C4T `+ _-2 4 i c; r.( -i - L'EriD 3- e Nur pregn an t ABORT ED 0 y 1 0 0 El 1 10 0 *3 0 0 0 E S u R I ITPLAN Ok P R h 1 1 ON i A f'lOr-J L U T E A I FES S IT E S MEAN. F E T U S WT< AVG H F O 1 I-' 10 !1 0 '1 16 1- 0 1 0 0 P'l pi . 'J L" 6 JO 2 4 4 1 2 7 . 5 E. 4 1 . S 44 7 33. 0 1 0 2 6 . 7 0.6 . 2 2 7 . 1 ' 3 IS . 0 4 _ A 4 2 6 . 5* 4 1 . t: -S. 5 4 0 . 2 2 8 . 4 - 4 4 0 0 4 7. 4 At 4 4 . S 4 4 3. 7 & 2 4. .4 3 4 0 2 6 . 0 0. 4 4 . 4 4 0 . 4 4 2. S B ST. 0 40. 1 _4 2 r SO. 0 4 4 . 1 27. 5 lb 4 . 3 0 . 0 *- 4 6 . U 4 5 . 7 4 6 . 2 003103 5 mg/kg/day Appendix VI (Continued) Oral Teratology Study of T-3141CoC in Rabbits Individual Litter Data With Mean Fetus Weights 22 ANI HAL V I A B L E F E T U S E S DEAL:* M F TOTAL FETUSES F.'ESOF: I MF'LAN CORF'RA F T I ON T A T IO N L U T E A SITES SITES MEAN F E T U S WT AVG MF -'lb -IB J.B -TB - j_B 8 :i.6 x B 1 IS'X tz'` -lo X tL 'K XX 'I t XB IB 1 11x0 2331 X X-X X L i 1'! . . 's 23 4 7 X LrO X 0 3? 1 x ts-B Lf _*SU 1 O1 & 2 FOB 2 710 2 71 L 712 2i l l X r' XX XX X i1 2 if. X i.;j X o' r" NOT F'F:EGNAN7 f .j'_l 'i !~"RB xf`:Hfl } NOT F'F.EuNAN i iy(_i T F F'E'j NANT 4X s' l.-'EAL ,-j 1 o Ni.i ! F 'R E j NAN 1 X1 3 -* X ' X '-J B X- 3 X- 4 3 NOT F R E u N A N 1 o 0 0 0 0 0 0 0 J 0 0 0B 1X 0s lo 3 4 . X 3 1 x x b 01 X S 0 3 0 2 . x 13- B o- 3 373 3 xo*. i r X- r*. X 3 7 . 7 3 5 . 3 0 1r 5 1 0. 0 X if.. 5 C*j 4 0 . 1 4 0. x x 3 J 0 X- X- 4 8 X- 4 8. 5 4 7. i 0r T X-B . 0 3 8 . 3 x 5. 3 1 3 10 2 : 1 3 _ 4. i 0 3 13- X-b . r x 3 5 3 ? . 01 0T 3 4-1 0 4 x . 6 4 4 . 003104 1.5 mg/kg/day $W yA V jlll4 & g3 Appendix VI (Concluded) Oral Teratology Study of T-3141COC in Rabbits Individual Litter Data With Mean Fetus Weights ANIMAL VIABLE FETUSES DEAD M F TOTAL FETUSES F'ESOR IMPLAN CO R P R A PTION TATION LUTE A SITES SITES MEAN FETUS NT AVG M F ib 2 s s i B y "^ IE- 2 2 6 LB 2 2 4 9 IB 2250 3 2251 :,B 2 2 5 2 _K 2697 .uB 6 9 6 .lI* i, *^i .6 2FO 0 -B 2 7 1 2 f-, 2 7 1 4 2715 .8 2 7 1 6 B 2723 .B 2 7 2 4 NOT PREGNANT NOT PREGNANT DEAD NOT PREGNANT DEAD NOT PREGNANT NOT PREGNANT S- s b 4 15 42 ~ "< 6 CT DEAD 25 42 54 DEAD ABORTED r' 7 3 0 0 0 0 0 0 0 17 05 1r 05 Q 4 6 . 2 4 6 . 1 4 6. _i5 2 4 . 7 *4 3 8 . 1 \ 40. 4 40. 1 40. 3 i' 3 8 . 8 4 0 . 8 3 5 . S Ei r c i *24 !-) 2 7 . A 2 9 7 11. 3 r" 4 0 . 1 2-9 2 4 1 . 1 0 9 1 2 f'. t` 2 8 . 1 3 7 . 1 003105 Dose Group - 0 mg/kg/day Dam No. Total fetuses examined Small Appendix Vll Oral Teratology Study of T-3141CoC in Rabbits Number of Fetuses by Dam With Gross Findings 2321 5 2322 3 2323 7 2 2324 1 2338 7 1 2339 1 2686 7 2703 1 2704 6 2717 5 2718 6 Dose Group - 50 mg/kg/day Dam No. Total fetuses examined Small 2325 5 2326 6 2328 7 1 2341 6 2342 4 2643 5 2644 1 2689 3 2690 8 2691 5 2692 9 2705 8 2706 2 2708 5 Dose Group - 5 mg/kg/day Dam No. Total fetuses examined Small 2329 8 1 2330 2 2331 8 2332 7 2693 7 2695 6 2709 3 2710 7 2711 7 1 2712 9 2721 7 Dose Group - 1.5 mg/kg/day Dam No. Total fetuses examined Small Clubbed forepaw 2697 6 2698 5 1 2699 6 2700 5 2714 7 2 2715 7 2716 9 to 003106 Dose Group - 0 mg/kg/day Dam No. Total fetuses examined Appendix VIII Oral Teratology Study of T-3141CoC in Rabbits Number of Fetuses by Dam With Internal Findings 2321 2322 2323 2324 2338 2339 2686 2703 2704 2717 2718 537171716 56 Dose Group - 50 mg/kg/day Dam No. Total fetuses examined 2325 2326 2328 2341 2342 2343 2344 2689 2690 2691 2692 2705 2706 2708 56 764 5138 59825 Dose Group - 5 mg/kg/day Dam No. Total fetuses examined 2329 2330 2331 2332 2693 2695 2709 2710 2711 2712 2721 828 776 3779 7 Dose Group - 1.5 mg/kg/day Dam No. Total fetuses examined 2697 2698 2699 2700 2714 2715 2716 6 565 779 25. 003107 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 uiai itirdtoioyy Study of T-3141CoC in Rabbits Number of Fetuses by Dam With Skeletal Findings 2321 2322 2323 2324 2338 2339 2686 2703 2704 2717 2718 5 37171716 56 124 4 4 3 1 1 1 1 2 11 1 112 1 1 1111 11 11 2 1 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 rios 13 ribs spurred 2325 5 4 1 2326 6 2 1 1 1 3 2 2328 7 2 1 7 2341 6 3 3 3 2 2342 4 0 1 3 1 2343 5 2 3 1 1 2344 1 2689 3 1 3 2690 8 1 5 1 2 2691 5 1 2 2692 9 2705 8 4 1 1 2706 2 1 1 2708 5 1 1 3 1 KJ 003108 003109 Dose Group - 5 mg/kg/day Dam No. Number of fetuses examined Fontanelle not closed sternebrae not ossified Sternebrae asymmetrical One sternebrae missing 13 ribs 13 ribs spurred 13 ribs floating Oral Teratology Study of T-3141CoC in Rabbits Number of Fetuses by Dam With Skeletal Findings 2329 8 2 1 7 1 2330 2 1 1 2331 8 5 3 3 2332 7 2 3 3 2693 7 3 3 1 2695 6 1 1 1 3 1 2709 3 1 2710 7 1 3 3 1 1 2 2711 7 2 1 2 2712 9 5 2 1 3 2 1 2721 7 1 3 Dose Group - 1.5 mg/kg/day Dam No. Number of fetuses examined Fontanelle not closed Holes in both parietals Sternebrae not ossified Sternebrae asymmetrical Extra sternebrae 13 ribs 13 ribs spurred 13 ribs floating 2697 6 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 N> -4 DISTRIBUTION EIST M. T. Case * G Gortner (Original + 1) P. Keller (QA File) E. G. Lamprecht E. L. Wutsch R. A. Nelson -+ R. E. Ober W. C. McCormick -* F. D. Griffith (2) tt. H. Pearl son G. R. Steffen + J. D. Henderson -* K. L. Ebbens 003110