TABLE OF CONTENTS · 2017. 11. 15. · PROSTATE (% TBW) MEAN SEMINAL VESICLES WITH FLUID (% TBW) MEAN WITHOUT FLUID (% TBW) MEAN ALL WEIGHTS ARE MEASURED IN GRAMS SUMMARY - 2008 to

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TABLE OF CONTENTS

Sprague Dawley and Wistar Rats

Crl:CD(SD) Rats HCD1 Date Range Page 1. Hamilton-Thorne Sperm Evaluation 1998 - 2016 4 2. Sperm Morphology 2008 - 2015 5 3. Male Fertility/ Male Reproductive Organ Weights

and Ratios 2008 - 2016 6 4. Female Estrous Cycling and Mating/Fertility 2008 - 2016 9 5. DG 13 Maternal Reproductive Indices 2011 - 2014 11 6. DG 20 Maternal Reproductive Indices 2011 - 2014 13 7. DG 20 Fetal Gross External Alterations 2011 - 2014 15 8. DG 21 Maternal Reproductive Indices 2011 - 2015 16 9. DG 21 Litter and Fetal Alterations Summary 2011 - 2015 18 10. DG 21 Fetal Gross External Alterations 2011 - 2015 19 11. DG 21 Fetal Soft Tissue Alterations 2011 - 2015 21 12. DG 21 Fetal Skeletal Alterations 2011 - 2015 23 13. DG 21 Fetal Ossification Site Averages 2011 - 2015 29 14. Natural Delivery Data 2011 - 2015 30

1 Additional HCD endpoints and years are available upon request.

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Wistar [Crl:WI(Han)] Rats HCD Date Range Page 15. DG 20 and 21 Maternal Reproductive Indices 2003 - 2016 42 16. DG 20 and 21 Litter and Fetal Alterations Summary 2003 - 2014 46 17. DG 20 and 21 Fetal Gross External Alterations 2003 - 2016 47 18. DG 20 and 21 Fetal Soft Tissue Alterations 2003 - 2016 49 19. DG 20 and 21 Fetal Skeletal Alterations 2003 - 2016 51 20. DG 20 and 21 Fetal Ossification Site Averages 2003 - 2016 54

Contact: Elise M. Lewis, PhD Director of Reproductive and Neurobehavioral Toxicology

Charles River Laboratories, Inc., Pennsylvania Phone: 267.532.3741 Fax: 215.443.8587 Email: [email protected]

HAMILTON-THORNE SPERM EVALUATIONHISTORICAL CONTROL DATA

Crl:CD(SD) RATS

HAMILTON-THORNE IVOSCODE:PROTOCOLDRAFT FINAL REPORT MAIL DATE:TYPE OF STUDY:

INCLUDED IN ANALYSIS N

LEFT CAUDA SPERM MOTILITY (1998-2002)

NUMBER MOTILE MEAN

MOTILE PERCENT MEAN

STATIC COUNT (NONMOTILE) MEAN

TOTAL COUNT MEAN

VAS DEFERENS (LEFT) SPERM MOTILITY

NUMBER MOTILE MEAN

MOTILE PERCENT MEAN


TOTAL COUNT MEAN

VAS DEFERENS (BILATERAL) SPERM MOTILITY

NUMBER MOTILE MEAN

MOTILE PERCENT MEAN


TOTAL COUNT MEAN

CAUDA EPIDIDYMAL SPERM COUNT

SPERM COUNT (10 fields evaluated) MEAN

SPERM COUNT (20 fields evaluated) MEAN

DENSITY MEAN

SPERM CONCENTRATION MEAN

TESTICULAR SPERM COUNT

SPERMATID COUNT (10 fields evaluated) MEAN

SPERMATID DENSITY MEAN

SPERMATID CONCENTRATION MEAN

SUMMARYOnly includes audited studies

5212 TOTAL RATSNO. STUDIES

AVERAGE MINIMUM MAXIMUM INCLUDED22.6 5 33 230

352.1 226.6 565.8 40

79.4 62.5 89.5 41

87.4 22.1 181.5 40

439.5 251.1 740.0 40

365.0 209.4 583.6 109

90.9 77.1 96.4 108

34.7 13.8 99.4 108

400.4 281.3 617.4 108

480.3 308.4 821.1 72.0

90.4 80.3 96.0 81.0

50.5 15.6 101.8 72.0

530.4 348.4 852.6 72.0

132.1 55.3 229.8 183

277.7 63.8 410.5 38

1137.8 599.6 1713.1 230.0

8.2 6.4 10.8 3

73.2 18.5 154.8 25

124.9 27.3 227.1 26

2.1 2.0 2.1 2

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SPERM MORPHOLOGY

HISTORICAL CONTROL DATA

Crl:CD(SD) RATS

Audited studies highlighted in green

CODE:

DRAFT FINAL REPORT MAIL DATE:

TYPE OF STUDY:

RATS TESTED N

PERIOD: 2008 - 2015

CAUDA EPIDIDYMAL SPERM MORPHOLOGY

Normal MEAN

Percent abnormal MEAN

No hook MEAN

Excessive hook MEAN

No head MEAN

Detached head MEAN

Amorphous MEAN

Pin head MEAN

Two heads & tails MEAN

Short sperm head MEAN

Banana MEAN

Broken flagellum MEAN

Coiled flagellum MEAN

Bent flagellum MEAN

Bent flagellum tip MEAN

Other MEAN

SUMMARY

Only includes audited studies

TOTAL MALE RATS 1339

AVERAGE MINIMUM MAXIMUM NO. STUDIES INCL.

IN ANALYSIS

190.6 168.8 202.1 62

4.8 0.2 15.8 62

0.2 0.0 4.2 45

0.1 0.0 2.4 34

3.1 0.0 12.3 59

5.9 0.5 19.4 60

0.1 0.0 1.0 35

0.0 0.0 0.1 31

0.3 0.0 7.9 28

0.2 0.0 5.4 37

0.0 0.0 0.6 28

0.4 0.0 2.5 59

0.0 0.0 0.2 47

0.0 0.0 0.3 45

0.0 0.0 0.0 32

0.1 0.0 2.9 22

6 65

MALE FERTILITY/ REPRODUCTIVE ORGAN WEIGHTS AND RATIOS HISTORICAL CONTROL DATA

Crl:CD(SD) RATS

CODE:PROTOCOL:GLP or Non-GLPFINAL DRAFT REPORT MAIL DATE:

RATS TESTED N

TERMINAL BODY WEIGHT (TBW) MEAN

TESTIS LEFT MEAN RIGHT MEAN PAIRED MEAN LEFT, MINUS TUNICA ALBUGINEA MEAN

EPIDIDYMIS LEFT MEAN RIGHT MEAN PAIRED MEAN

CAUDA EPIDIDYMIS LEFT MEANCAUDA EPIDIDYMIS RIGHT MEAN

PROSTATE MEAN

SEMINAL VESICLES WITH FLUID MEAN

WITHOUT FLUID MEAN

RATIO (%) ORG. WTS TO BODY WTS TESTIS (% TBW) LEFT MEAN RIGHT MEAN PAIRED MEAN LEFT, MINUS TUNICA ALBUGINEA MEAN

EPIDIDYMIS (% TBW) LEFT MEAN RIGHT MEAN PAIRED MEAN

CAUDA EPIDIDYMIS LEFT (% TBW) MEAN CAUDA EPIDIDYMIS RIGHT (% TBW) MEAN

PROSTATE (% TBW) MEAN

SEMINAL VESICLES WITH FLUID (% TBW) MEAN

WITHOUT FLUID (% TBW) MEAN

ALL WEIGHTS ARE MEASURED IN GRAMS

SUMMARY - 2008 to present

**Note that spreadsheet includes all males with repro. data (P, F1, F2 generations and all ages)

NO. STUDIESAVERAGE MINIMUM MAXIMUM INCLUDED

4211 = TOTAL RATS TESTED

550.9 317.7 725.3 215

1.831 1.330 2.220 1341.835 1.350 2.071 1343.645 2.950 4.080 831.685 1.675 1.694 2

0.7332 0.260 0.870 1290.7468 0.270 0.890 1271.4760 0.680 1.730 81

0.3157 0.130 0.392 990.5437 0.336 0.751 2

1.2655 0.510 1.735 126

1.9782 0.810 3.530 116

0.9480 0.430 2.200 101

0.3373 0.248 0.489 1340.3377 0.256 0.524 1340.6792 0.550 0.934 800.3115 0.303 0.320 2

0.1321 0.079 0.161 1290.1345 0.082 0.158 1270.2896 0.185 1.710 78

0.0561 0.039 0.068 990.1010 0.063 0.139 2

0.2304 0.159 0.296 126

0.3595 0.249 0.615 115

0.1717 0.103 0.381 100

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Crl:CD(SD) RATS


BRAIN WEIGHT (BRW) MEAN

RATIO (%) ORG. WTS TO BRAIN WTS TESTIS (% BRW) LEFT MEAN RIGHT MEAN PAIRED MEAN LEFT, MINUS TUNICA ALBUGINEA MEAN

EPIDIDYMIS (% BRW) LEFT MEAN RIGHT MEAN PAIRED MEAN CAUDA EPIDIDYMIS LEFT (% BRW) MEAN

PROSTATE (% BRW) MEAN SEMINAL VESICLES WITH FLUID (% BRW) MEAN

WITHOUT FLUID (% BRW) MEAN

ALL WEIGHTS ARE MEASURED IN GRAMS




2.25 1.990 2.470 66

81.41 71.85 95.90 3281.66 71.88 90.70 32

156.95 143.54 171.80 30159.44 159.44 159.44 1

32.91 19.09 37.53 2733.38 18.73 38.60 2760.93 40.40 72.70 3113.37 5.92 15.80 17

54.16 38.90 75.70 29

87.64 59.10 110.70 17

41.68 29.80 53.00 13

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Crl:CD(SD) RATS


RATS IN COHABITATION N

DAYS IN COHABITATION MEAN

RATS THAT MATED N%

RATS WITH CONFIRMED MATING DATES N

FERTILITY INDEX1 NN%

RATS MATING DAYS 1-7 N

%

DAYS 8-14 N%

DAYS 15-21 N%

MATED WITH SECOND FEMALE DAYS 1-7 N

%

DAYS 8-14 N%

DAYS 15-21 N%

RATS PREGNANT/RATS IN COHABITATION N

N%

1 Number of pregnancies/number of rats that mated




4138 = TOTAL RATS IN COHABITATION

2.8 1.3 4.3 187

21.7 6 34 18797.9 75.0 100.0 187

21.6 6 34 187

20.4 6 31 18721.7 6 34 18794.1 75 100 187

21.2 6 34 18097.8 84 100 180

1.3 1 4 616.0 3.3 16.0 61

1.0 1 1 24.0 4.0 4.0 2

1.0 1 1 24.3 4.2 4.4 2

1.0 1 1 336.1 4.0 100 3

1.0 1 1 14.0 1.0 4.0 1

20.3 6 31 18022.0 8 34 18092.3 63 100 180

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FEMALE ESTROUS CYCLING AND MATING/ FERTILITY HISTORICAL CONTROL DATA

Crl:CD(SD) RATS

CODE:PROTOCOL :TYPE OF STUDY:


ESTROUS CYCLING OBSERVATIONS

RATS EVALUATED N

PREDOSE ESTROUS CYCLING

ESTROUS STAGES/14 DAYS MEAN

STAGES IN INTERVAL MEAN

RATS WITH 6 OR MORE CONSEC. DAYS OF DIESTRUS N

RATS WITH 6 OR MORE CONSEC. DAYS OF ESTRUS N

RATS EVALUATED N

PRECOHABITATION ESTROUS CYCLING

ESTROUS STAGES/7 DAYS MEAN ESTROUS STAGES/9 DAYS MEAN ESTROUS STAGES/10 DAYS MEAN ESTROUS STAGES/13 DAYS MEAN ESTROUS STAGES/14 DAYS MEAN ESTROUS STAGES/21 DAYS MEAN ESTROUS STAGES/22 DAYS MEAN

STAGES IN INTERVAL MEAN

RATS WITH 6 OR MORE CONSEC. DAYS OF DIESTRUS N

RATS WITH 6 OR MORE CONSEC. DAYS OF ESTRUS N

SUMMARY - 2008 to presentOnly includes audited studies

TOTAL RATS WITH ESTROUS OBSERVATIONS

NO. STUDIESMINIMUM MAXIMUM INCLUDED

8 50 135

2.4 5.3 68

1.7 3.8 23

1 6.0 14

5 5.0 1

8 30.0 38

1.6 1.9 52.2 2.2 12.1 2.2 22.5 3.5 62.7 3.6 894.1 4.9 54.5 5.1 2

3.0 3.4 17

1 8.0 37

1 2 2

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FEMALE ESTROUS CYCLING AND MATING/ FERTILITY HISTORICAL CONTROL DATA

Crl:CD(SD) RATS

CODE:PROTOCOL :TYPE OF STUDY:


RATS IN COHABITATION N

DAYS IN COHABITATION MEAN

RATS THAT MATED N%

RATS WITH CONFIRMED MATING DATES N

RATS MATED BY FIRST MALE DAYS 1-3 N

% DAYS 1-7 N

% DAYS 4-7 N

% DAYS 8-14 N

% DAYS 15-21 N

%

RATS MATED BY SECOND MALE DAYS 8-14 N

%

DAYS 15-21 N%

FERTILITY INDEX1 NN%

RATS PREGNANT/RATS IN COHABITATION N

N%

1 Number of pregnancies/number of rats that mated

SUMMARY - 2008 to presentOnly includes audited studies

TOTAL RATS WITH ESTROUS OBSERVATIONS

NO. STUDIES

TOTAL RATS

1.4 7 189

6.0 50 18675.0 100 186

6.0 50 188

6 6 167 67 17 49 185

64 100 1851 1.0 1

11 11.1 11 4.0 641 16.0 64

1 9 141 36 14

1 2 251 8 25

48.0 48 1896.0 50 189

76.0 100 189

6.0 48 1858.0 50 185

75.0 100 185

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SUMMARY OF REPRODUCTIVE INDICES Crl:CD(SD) RATS DAY 13 CAESAREAN-SECTION

PERIOD: JUNE 2011 - DECEMBER 2014

NUMBER OF STUDIES 37

NUMBER OF RATS: TESTED 848 PREGNANT 775 FOUND DEAD 8*

NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING 773

RANGE/STUDY MEAN or % MEAN or %

% PREGNANT 94.2 (17.4-100) AVERAGE NO. CORPORA LUTEA 15.6 (9.0-17.2) AVERAGE NO. IMPLANTATIONS 14.9 (4.8-16.9) AVERAGE % PREIMPLANTATION LOSS 5.2 (2.6-27.5)

AVERAGE NO. VIABLE EMBRYOS 14.0 (1.8-16.0) AVERAGE NO. NONVIABLE EMBRYOS 0.9 (0.4-4.2)

AVERAGE % POSTIMPLANTATION LOSS 6.5 (3.4-40.6)

DAMS WITH ANY NONVIABLE EMBRYOS 51.7 (36.8-100.0)

* Four were found dead and two were unscheduled euthanized.

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19 18 14 1211



DAMS WITH ALL NONVIABLE EMBRYOS 0.5 (0-50.0)

AVERAGE % DAMS WITH VIABLE EMBRYOS 99.5 (50.0-100)

PLACENTAE APPEARED NORMAL 100.0 --

% NONVIABLE EMBRYOS/LITTER 6.3 (2.8-73.6)

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20 19 15 1312


PERIOD: JANUARY 2011 - JULY 2014

NUMBER OF STUDIES 5

NUMBER OF RATS:TESTED 124

PREGNANT 121FOUND DEAD 0

ABORTED 0DELIVERED 0

NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING 121

NUMBER OF RATS WITH SINGLE CONCEPTUS LITTER:

LIVE 0RESORBED 0ABORTED 0


% PREGNANT 97.7 (92.0-100.0) AVERAGE NO. CORPORA LUTEA 15.6 (14.7-16.2) AVERAGE NO. IMPLANTATIONS 14.5 (13.7-14.9) AVERAGE % PREIMPLANTATION LOSS 6.2 (2.9-10.1)

AVERAGE LITTER SIZE

AVERAGE NO. LIVE CONCEPTUSES 13.9 (13.1-14.3) AVERAGE NO. DEAD CONCEPTUSES 0.0 --

AVERAGE NO. RESORPTIONS 0.6 (0.4-1.0) AVERAGE NO. EARLY RESORPTIONS 0.6 (0.4-1.0) AVERAGE NO. LATE RESORPTIONS 0.0 (0.0-0.1) AVERAGE % POSTIMPLANTATION LOSS 4.5 (2.6-6.8)

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21 20 16 1413



AVERAGE % DAMS WITH ANY RESORPTIONS 34.7 (34.8-52.0)

AVERAGE % DAMS WITH ALL CONCEPTUSES RESORBED 0.0 --

AVERAGE % DAMS WITH VIABLE FETUSES 100.0 --

AVERAGE % DAMS WITH NORMAL PLACENTAE 99.2 (96.0-100.0)

AVERAGE SEX RATIO (% MALES/LITTER) 49.4 (46.6-53.3) FETAL BODY WEIGHT AVERAGE FOR MALES (G) 3.97 (3.84-4.03)

AVERAGE FOR FEMALES (G) 3.75 (3.67-3.81)

AVERAGE % DEAD OR RESORBED CONCEPTUSES/LITTER 4.5 (2.6-6.8)

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22 21 17 1514

SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS Crl:CD(SD) RATS DAY 20 CAESAREAN-SECTION

PERIOD: JANUARY 2011 - JULY 2014

NO. STUDIES INCLUDED 5NO. LITTERS EXAMINED 122NO. LIVE FETUSES EXAMINED 1690

ALTERATION RANGE /STUDYN % N %

BODYTrunk short L 1 0.82 0-1 (0-4.0)

F 4 0.24 0-4 (0-1.1)

FORE AND/OR HINDLIMB(S)

Digits extra L 1 0.82 0-1 (0-4.0)F 4 0.24 0-4 (0-1.1)

Malpositioned L 1 0.82 0-1 (0-4.0)F 4 0.24 0-4 (0-1.1)

Fused digits L 1 0.82 0-1 (0-4.0)F 4 0.24 0-4 (0-1.1)

Digits short L 1 0.82 0-1 (0-4.0)F 4 0.24 0-4 (0-1.1)

TAILShort L 1 0.82 0-1 (0-4.0)

F 1 0.06 0-1 (0-0.3)

L: LITTER INCIDENCEF: FETAL INCIDENCE

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23 22 18 1615

SUMMARY OF REPRODUCTIVE INDICESCrl:CD(SD) RATS

DAY 21 CAESAREAN-SECTION

PERIOD: JUNE 2011 - JANUARY 2015FULL DOSE-RANGE

STUDIES STUDIES

NUMBER OF STUDIES 45 27

NUMBER OF RATS:TESTED 1121 194PREGNANT 1084 190FOUND DEAD 3* 0ABORTED 0 0DELIVERED 5 1

NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING 1077 189

NUMBER OF RATS WITH SINGLE CONCEPTUS LITTER:LIVE 2 0RESORBED 0 0ABORTED 0 0

RANGE/STUDY RANGE/STUDY MEAN or % MEAN or % MEAN or % MEAN or %

% PREGNANT 96.9 (84.0-100) 98.2 (83.3-100) AVERAGE NO. CORPORA LUTEA 14.7 (12.5-16.4) 14.5 (11.4-16.9) AVERAGE NO. IMPLANTATIONS 14.1 (11.5-16.0) 13.8 (10.1-16.3) AVERAGE % PREIMPLANTATION LOSS 4.1 (0.6-10.3) 5.3 (0.0-26.6)

AVERAGE LITTER SIZE

AVERAGE NO. LIVE FETUSES 13.5 (10.7-15.0) 13.2 (9.6-15.7) AVERAGE NO. DEAD FETUSES 0.0 --- 0.0 ---

AVERAGE NO. RESORPTIONS 0.6 (0.2-1.1) 0.6 (0.0-2.0) AVERAGE NO. EARLY RESORPTIONS 0.6 (0.2-1.1) 0.6 (0.0-2.0) AVERAGE NO. LATE RESORPTIONS 0.0 (0.0-0.1) 0.0 (0.0-0.1)

AVERAGE % POSTIMPLANTATION LOSS 4.1 (1.4-7.3) 4.2 (0.0-16.2)

* Three were unscheduled euthanasia

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24 23 19 1716

SUMMARY OF REPRODUCTIVE INDICESCrl:CD(SD) RATS


FULL DOSE-RANGE STUDIES STUDIES


AVERAGE % DAMS WITH ANY RESORPTIONS 40.8 (18.2-62.5) 34.4 (0.0-66.7)

AVERAGE % DAMS WITH ALL CONCEPTUSES RESORBED 0.0 --- 0.0 ---

AVERAGE % DAMS WITH VIABLE FETUSES 100.0 --- 100.0 ---

AVERAGE % DAMS WITH NORMAL PLACENTAE 106.7 (95.4-100.0) 109.2 ---

AVERAGE SEX RATIO (% MALES/LITTER) 50.6 (45.2-56.3) 46.8 (37.2-63.0) AVERAGE FETAL BODY WEIGHT (G) 5.67 (5.32-6.20) 5.20 (5.39-6.21) AVERAGE FOR MALES (G) 5.80 (5.44-6.31) 5.54 (5.54-6.24)

AVERAGE FOR FEMALES (G) 5.52 (5.16-6.05) 5.26 (5.16-6.11)

AVERAGE % DEAD OR RESORBED CONCEPTUSES/LITTER 4.1 (1.4-7.3) 4.2 (0.0-16.2)

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25 24 20 1817

LITTER AND FETAL ALTERATIONS SUMMARY Crl:CD(SD) RATS DAY 21 CAESAREAN-SECTION

PERIOD: JUNE 2011 - JANUARY 2015

NUMBER OF STUDIES: 39

NUMBER OF LITTERS EVALUATED: 845

NUMBER OF FETUSES EVALUATED (LIVE): 11464


LITTERS WITH FETUSES WITHANY ALTERATION OBSERVED % 25.4 (0.0-42.1)

FETUSES WITH ANYALTERATION OBSERVED % 2.3 (0.0-4.8)

% FETUSES WITH ANYALTERATION/LITTER MEAN 2.3 (0.0-5.0)

11

26 25 21 1918

SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS Crl:CD(SD) RATS - DAY 21 CAESAREAN-SECTION


STUDIES STUDIES

NO. STUDIES INCLUDED 47 24NO. LITTERS EXAMINED 1075 165NO. LIVE FETUSES EXAMINED 14352 2171

ALTERATION RANGE /STUDY RANGE /STUDYN % N % N % N %

HEADExencephaly L 2 0.19 0-1 (0-5.0) 0 --- --- ---

F 2 0.01 0-1 (0-0.3) 0 --- --- ---Fleshy protrusion L 1 0.09 0-1 (0-4.3) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Irregular shape L 1 0.09 0-1 (0-4.3) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Domed L 1 0.09 0-1 (0-4.5) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Meningocele L 2 0.19 0-1 (0-4.5) 0 --- --- ---

F 2 0.01 0-1 (0-0.4) 0 --- --- ---

EYE One or both eye bulges L 6 0.37 0-1 (0-5.6) 1 0.61 0-1 (0-25.0) depressed F 6 0.03 0-1 (0-0.4) 1 0.05 0-1 (0-1.9)One or both eye lids L 1 0.09 0-1 (0-5.6) 0 --- --- --- open F 1 0.01 0-1 (0-0.4) 0 --- --- ---

SNOUTShort L 1 0.09 0-1 (0-5.6) 0 --- --- ---

F 1 0.01 0-1 (0-0.4) 0 --- --- ---Cleft L 1 0.09 0-1 (0-4.3) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---

PALATE Cleft L 1 0.09 0-1 (0-4.2) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---

TONGUEProtruded L 2 0.19 0-1 (0-5.6) 0 --- --- ---

F 2 0.01 0-1 (0-0.4) 0 --- --- ---Absent L 1 0.09 0-1 (0-4.2) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---

MOUTHSmall oral opening L 1 0.09 0-1 (0-4.2) 2 1.21 0-1 (0-25.0)

F 1 0.01 0-1 (0-0.3) 2 0.09 0-1 (0-1.9)


12

27 26 22 2019

SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS Crl:CD(SD) RATS - DAY 21 CAESAREAN-SECTION



JAW Micrognathia L 2 0.19 0-1 (0-4.2) 1 0.61 0-1 (0-16.7)

F 2 0.01 0-1 (0-0.3) 1 0.05 0-1 (0-1.4)Agnathia L 1 0.09 0-1 (0-4.2) 1 0.61 0-1 (0-25.0)

F 1 0.01 0-1 (0-0.3) 1 0.05 0-1 (0-1.9)

EARSLow set L 0 --- --- --- 1 0.61 0-1 (0-25.0)

F 0 --- --- --- 1 0.05 0-1 (0-1.9)

BODY Umbilical hernia L 2 0.19 0-1 (0-4.5) 0 --- --- ---

F 2 0.01 0-1 (0-0.4) 0 --- --- ---Edema L 1 0.09 0-1 (0-4.2) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Trunk short L 3 0.28 0-1 (0-5.6) 0 --- --- ---

F 3 0.02 0-1 (0-0.4) 0 --- --- ---Craniorachischisis L 2 0.19 0-1 (0-5.6) 0 --- --- ---

F 2 0.01 0-1 (0-0.4) 0 --- --- ---Spina bifida L 1 0.09 0-1 (0-5.0) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Abdominal distension L 0 --- --- --- 1 0.61 0-1 (0-10.0)

F 0 --- --- --- 1 0.05 0-1 (0-0.6)

FORE AND/OR HINDLIMB(S)Digit(s), extra L 1 0.19 0-1 (0-4.0) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Paw(s), flexed L 1 0.09 0-1 (0-5.0) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Limb(s), short L 0 --- --- --- 1 0.61 0-1 (0-10.0)

F 0 --- --- --- 1 0.05 0-1 (0-0.6)Limb(s), rotated L 2 0.28 0-1 (0-4.5) 0 --- --- ---

F 2 0.02 0-1 (0-0.3) 0 --- --- ---Limb(s), flexed L 1 0.09 0-1 (0-4.2) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---

ANUSNo opening present L 1 0.09 0-1 (0-4.3) 1 0.61 0-1 (0-16.7)

F 1 0.01 0-1 (0-0.3) 1 0.05 0-1 (0-1.5)

TAILShort L 1 0.09 0-1 (0-4.2) 0 --- --- ---

F 1 0.01 0-1 (0-0.3) 0 --- --- ---Absent L 1 0.09 0-1 (0-4.0) 1 0.61 0-1 (0-16.7)

F 1 0.01 0-1 (0-0.3) 1 0.05 0-1 (0-1.5)


13

28 27 23 2120

SUMMARY OF FETAL SOFT TISSUE ALTERATIONS Crl:CD(SD) RATS


PERIOD: JUNE 2011 - JANUARY 2015 FULL DOSE-RANGE

STUDIES STUDIES

NO. STUDIES INCLUDED 34 8NO. LITTERS EXAMINED 945 59NO. FETUSES EXAMINED (HEAD AND BODY) 6310 646 NO. FETUSES WITH HEADS ONLY EXAMINED 149 -- NO. FETUSES WITH BODIES ONLY EXAMINED 162 --

RANGE/STUDY RANGE /STUDYALTERATION N % N % N % N %

BRAIN Lateral ventricles, slight L 3 0.32 0-1 (0-5.3) 0 --- --- --- dilation F 3 0.05 0-1 (0-0.8) 0 --- --- ---Lateral ventricles, moderate L 3 0.32 0-1 (0-4.5) 1 1.69 0-1 (0-10.0) dilation F 3 0.05 0-1 (0-0.6) 1 0.15 0-1 (0-1.4)

EYE(S)Retina folded in one or both L 2 0.21 0-1 (0-5.3) 1 1.69 0-1 (0-10.0)

F 2 0.03 0-1 (0-0.8) 1 0.15 0-1 (0-1.4)Malpositioned L 1 0.11 0-1 (0-4.2) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---Cup irregular L 1 0.11 0-1 (0-4.2) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---Microphthalmia L 7 0.74 0-3 (0-12.5) 2 3.39 0-1 (0-16.7)

F 7 0.11 0-3 (0-1.9) 2 0.31 0-1 (0-1.4)

TONGUESmall L 1 0.11 0-1 (0-4.2) 1 1.69 0-1 (0-16.7)

F 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-1.4)Absent L 1 0.11 0-1 (0-4.2) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---

PALATEIrregulary Shaped L 1 0.11 0-1 (0-4.2) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---

NASOPHARYNXMisshapen L 1 0.11 0-1 (0-4.2) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---

HEARTInterventricular septal defect L 2 0.21 0-1 (0-4.3) 0 --- --- ---

F 2 0.03 0-1 (0-0.6) 0 --- --- ---

VESSELSInnominate artery, absent L 4 0.42 0-1 (0-4.5) 1 1.69 0-1 (0-10.0)

F 4 0.06 0-1 (0-0.6) 1 0.15 0-1 (0-1.3)Aorta passes dorsal to the L 1 0.11 0-1 (0-4.0) 0 --- --- --- trachea and esophagus F 1 0.02 0-1 (0-0.6) 0 --- --- ---


14

29 28 24 2221

SUMMARY OF FETAL SOFT TISSUE ALTERATIONS Crl:CD(SD) RATS




VESSELS (CONT.)Vessels arise in incorrect order L 1 0.11 0-1 (0-4.0) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---Right subclavian passes dorsal L 1 0.11 0-1 (0-4.3) 0 --- --- --- to trachea and esophagus F 1 0.02 0-1 (0-0.6) 0 --- --- ---Right subclavian arises to the L 1 0.11 0-1 (0-4.3) 0 --- --- --- left of left subclavian F 1 0.02 0-1 (0-0.6) 0 --- --- ---Pulmonary artery constricted L 1 0.11 0-1 (0-4.3) 0 --- --- ---

F 1 0.02 0-1 (0-0.6) 0 --- --- ---Transposed L 2 0.21 0-1 (0-4.0) 0 --- --- ---

F 2 0.03 0-1 (0-0.7) 0 --- --- ---

INTESTINESPortion protrudes through L 1 0.11 0-1 (0-4.0) 0 --- --- --- umbilicus F 1 0.02 0-1 (0-0.6) 0 --- --- ---

KIDNEYSSmall L 1 0.11 0-1 (0-4.5) 0 --- --- ---

F 1 0.02 0-1 (0-0.8) 0 --- --- ---


15

30 29 25 2322

SUMMARY OF FETAL SKELETAL ALTERATIONS Crl:CD(SD) RATS - DAY 21 CAESAREAN-SECTION


STUDIES STUDIES

NO. STUDIES INCLUDED 42 3NO. LITTERS EXAMINED 967 27NO. FETUSES EXAMINED 6719 205


SKULLFrontals: contain an interfrontal L 4 0.41 0-1 (0-5.0) 0 -- -- --

F 4 0.06 0-1 (0-0.8) 0 -- -- -- : incompletely ossified L 6 0.62 0-2 (0-10.5) 0 -- -- --

F 6 0.09 0-2 (0-1.5) 0 -- -- --Nasal: short L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Nasal - Frontal: suture, large L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-2 (0-1.1) 0 -- -- --Parietals: incompletely ossified L 8 0.83 0-2 (0-10.5) 0 -- -- --

F 8 0.12 0-2 (0-1.5) 0 -- -- --Interparietals: not ossified L 2 0.21 0-1 (0-5.0) 0 -- -- --

F 2 0.03 0-1 (0-0.7) 0 -- -- -- : incompletely ossified L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Eye socket: small L 4 0.41 0-1 (0-4.8) 0 -- -- --

F 4 0.06 0-1 (0-0.6) 0 -- -- --Palate: incompletely ossified L 2 0.21 0-1 (0-4.2) 0 -- -- --

F 2 0.03 0-1 (0-0.6) 0 -- -- -- : irregularly shaped L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Premaxilla: short L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Maxilla: short L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : split L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Mandible: short L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Squamosal: incompletely ossified L 15 1.55 0-2 (0-10.5) 0 -- -- --

F 16 0.24 0-2 (0-1.6) 0 -- -- --Zygomatic: incompletely ossified L 11 1.14 0-2 (0-8.0) 0 -- -- --

F 12 0.18 0-2 (0-1.1) 0 -- -- --


16

31 30 26 2423




SKULL (CONT.)Tympanic rings: incompletely L 1 0.10 0-1 (0-5.0) 0 -- -- -- ossified F 1 0.01 0-1 (0-0.7) 0 -- -- -- : close set L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Sphenoid: incompletely ossified L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Basisphenoid: irregularly shaped L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Basioccipital: irregularly shaped L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Skull: not ossified L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- -- : short L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- --Hyoid: not ossified L 3 0.31 0-2 (0-9.1) 0 -- -- --

F 3 0.04 0-2 (0-1.6) 0 -- -- --

VERTEBRAECervical: Arch, incompletely L 10 1.03 0-2 (0-8.0) 2 7.41 0-2 (0-25.0) ossified F 11 0.16 0-2 (0-1.2) 2 0.98 0-2 (0-3.3) : Reduced ventral processes, L 26 2.69 0-3 (0-13.6) 0 -- -- -- 6th F 29 0.43 0-5 (0-3.0) 0 -- -- -- : Arch, 7th had appearance L 2 0.21 0-2 (0-8.3) 0 -- -- -- like 6th F 2 0.03 0-2 (0-1.1) 0 -- -- -- : Arches, fused L 3 0.31 0-1 (0-4.2) 0 -- -- --

F 3 0.04 0-1 (0-0.6) 0 -- -- -- : Arches, open L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- -- : Arch, irregularly shaped L 5 0.52 0-1 (0-4.2) 0 -- -- --

F 5 0.07 0-1 (0-0.6) 0 -- -- -- : Lateral ossification site L 6 0.62 0-6 (0-27.3) 0 -- -- --

F 6 0.09 0-6 (0-3.7) 0 -- -- -- : Cervical rib present at 7th L 14 1.45 0-4 (0-18.2) 0 -- -- -- cervical vertebra F 15 0.22 0-5 (0-4.0) 0 -- -- -- : Hemivertebra L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- -- : Arch, small L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- --


17

32 31 27 2524




VERTEBRAE (CONT.)Thoracic: Centrum, bifid L 96 9.93 0-5 (0-34.8) 4 14.81 0-2 (0-25.0)

F 110 1.64 0-6 (0-5.7) 4 1.95 0-2 (0-3.3) : Centrum, unilateral L 2 0.21 0-1 (0-4.5) 0 -- -- -- ossification F 2 0.03 0-1 (0-0.8) 0 -- -- -- : Arches, fused L 3 0.31 0-1 (0-4.5) 0 -- -- --

F 3 0.04 0-1 (0-0.8) 0 -- -- -- : Arch, open L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- -- : 7 present L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : 11 present L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : Arch, small L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --

Lumbar: Centrum, bifid L 5 0.52 0-1 (0-4.5) 0 -- -- --F 5 0.07 0-1 (0-0.7) 0 -- -- --

: Centrum, unilateral L 1 0.10 0-1 (0-4.2) 0 -- -- -- ossification F 1 0.01 0-1 (0-0.6) 0 -- -- -- : Centrum, not ossified L 1 0.10 0-1 (0-5.0) 0 -- -- --

F 1 0.01 0-1 (0-0.8) 0 -- -- -- : Centrum, irregularly shaped L 1 0.10 0-1 (0-5.0) 0 -- -- --

F 1 0.01 0-1 (0-0.8) 0 -- -- -- : Centrum, small L 0 -- -- -- 1 3.70 0-1 (0-10.0)

F 0 -- -- -- 1 0.49 0-1 (0-1.2) : Centra fused L 1 0.01 0-1 (0-4.2) 0 -- -- --

F 1 0.10 0-1 (0-0.6) 0 -- -- -- : Arches and centrum fused L 1 0.10 0-1 (0-5.0) 1 3.70 0-1 (0-10.0)

F 1 0.01 0-1 (0-0.8) 1 0.49 0-1 (0-1.2) : Arch, irregularly shaped L 1 0.10 0-1 (0-5.0) 0 -- -- --

F 1 0.01 0-1 (0-0.8) 0 -- -- -- : Arch, open L 2 0.21 0-1 (0-5.0) 0 -- -- --

F 2 0.03 0-1 (0-0.7) 0 -- -- -- : 10 present L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : 1 present L 0 -- -- -- 1 3.70 0-1 (0-10.0)

F 0 -- -- -- 1 0.49 0-1 (0-1.2) : 5 present L 1 0.10 0-1 (0-5.0) 0 -- -- --

F 1 0.01 0-1 (0-0.8) 0 -- -- --


18

33 32 28 2625




VERTEBRAE (CONT.)Sacral: 0 present L 1 0.10 0-1 (0-5.0) 1 3.70 0-1 (0-10.0)

F 1 0.01 0-1 (0-0.8) 1 0.49 0-1 (0-1.2) : Arch, open L 2 0.21 0-1 (0-5.0) 0 -- -- --

F 2 0.03 0-1 (0-0.7) 0 -- -- -- : Arch, incompletely ossified L 1 0.10 0-1 (0-5.3) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- --

Caudal: 4 present L 1 0.10 0-1 (0-4.2) 0 -- -- --F 1 0.01 0-1 (0-0.6) 0 -- -- --

: Space L 0 -- -- -- 1 3.70 0-1 (0-10.0)F 0 -- -- -- 1 0.49 0-1 (0-1.2)

: Small L 0 -- -- -- 1 3.70 0-1 (0-10.0)F 0 -- -- -- 1 0.49 0-1 (0-1.2)

: Arch, open L 2 0.21 0-1 (0-5.0) 0 -- -- --F 2 0.03 0-1 (0-0.7) 0 -- -- --

Less than 26 pre-sacral vertebra L 1 0.10 0-1 (0-4.5) 0 -- -- --F 1 0.01 0-1 (0-0.8) 0 -- -- --

RIBS Cervical rib(s) present L 34 3.52 0-6 (0-15.8) 3 11.11 0-2 (0-20.0)

F 40 0.60 0-10 (0-2.3) 3 1.46 0-2 (0-2.7)One or more, wavy L 25 2.59 0-3 (0-12.5) 0 -- -- --

F 27 0.40 0-4 (0-2.4) 0 -- -- --One or more incompletely ossified L 27 2.79 0-3 (0-12.0) 0 -- -- -- (hypoplastic) or not ossified F 28 0.42 0-4 (0-2.4) 0 -- -- --Fused L 4 0.41 0-1 (0-4.5) 0 -- -- --

F 4 0.06 0-1 (0-0.8) 0 -- -- --Short L 21 2.17 0-2 (0-12.5) 1 3.70 0-1 (0-12.5)

F 22 0.33 0-2 (0-1.7) 1 0.49 0-1 (0-1.7)Thickened L 20 2.07 0-3 (0-12.5) 0 -- -- --

F 23 0.34 0-4 (0-2.4) 0 -- -- --6 present L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --7 present L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Bent L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Broad L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --


19

34 33 29 2726




RIBS (CONT.)Absent L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.5) 0 -- -- -- Split L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- 11 present L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- T14, short L 10 1.03 0-7 (0-31.8) 0 -- -- --

F 21 0.31 0-15 (0-12.1) 0 -- -- --

STERNEBRAEOne or more incompletely L 11 1.14 0-2 (0-9.1) 1 3.70 0-1 (0-12.5) ossified or not ossified F 12 0.18 0-3 (0-2.4) 1 0.49 0-1 (0-1.7)One or more asymmetric L 9 0.93 0-2 (0-8.3) 0 -- -- --

F 9 0.13 0-2 (0-1.1) 0 -- -- --Fused L 2 0.21 0-1 (0-4.2) 0 -- -- --

F 2 0.03 0-1 (0-0.6) 0 -- -- --

MANUBRIUMFused L 2 0.21 0-1 (0-4.2) 0 -- -- --

F 2 0.03 0-1 (0-0.6) 0 -- -- --Irregularly shaped L 2 0.21 0-1 (0-4.5) 0 -- -- --

F 2 0.03 0-1 (0-0.7) 0 -- -- --Duplicated L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- --

XIPHOIDIrregularly shaped L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- --Incompletely ossified L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.7) 0 -- -- --

SCAPULAEBody and Ala, bent L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --


20

35 34 30 2827




PELVISPubis, incompletely ossified L 5 0.52 0-2 (0-8.3) 0 -- -- --

F 5 0.07 0-2 (0-1.1) 0 -- -- --Ischium, incompletely ossified L 3 0.31 0-2 (0-8.3) 0 -- -- --

F 3 0.04 0-3 (0-1.6) 0 -- -- --Ilium, close set L 0 -- -- -- 1 3.70 0-1 (0-10.0)

F 0 -- -- -- 1 0.49 0-1 (0-1.2)Pelvis, close-set L 1 0.10 0-1 (0-4.0) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --

FORELIMB(S)Phalanx: absent L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : not ossified L 33 3.41 0-17 (0-77.3) 0 -- -- --

F 86 1.28 0-45 (0-35.4) 0 -- -- --Digit: absent L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : short L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --Metacarpal: fused L 1 0.10 0-1 (0-4.2) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- -- : less than the expected L 2 0.21 0-2 (0-9.1) 0 -- -- -- number are ossified F 2 0.03 0-2 (0-1.2) 0 -- -- -- : misaligned L 1 0.10 0-1 (0-4.5) 0 -- -- --

F 1 0.01 0-1 (0-0.6) 0 -- -- --

HINDLIMB(S)Digit: extra L 2 0.21 0-1 (0-4.2) 0 -- -- --

F 2 0.03 0-1 (0-0.6) 0 -- -- --Phalanx: extra L 2 0.21 0-1 (0-4.2) 0 -- -- --

F 2 0.03 0-1 (0-0.6) 0 -- -- --Metatarsal: not ossified L 9 0.93 0-5 (0-22.7) 0 -- -- --

F 13 0.19 0-7 (0-5.5) 0 -- -- --


21

36 35 31 2928

SUMMARY OF FETAL OSSIFICATION SITE AVERAGES SKELETAL AVERAGES Crl:CD(SD) RATS DAY 21 CAESAREAN-SECTION

PERIOD: JUNE 2011 - JANUARY 2015


FETUS/LITTER FETUS/LITTERSKELETAL AVERAGES MEAN RANGE/STUDY MEAN RANGE/STUDY

HYOID 0.99 (0.95-1.00) 1.00 --VERTEBRAE CERVICAL 7.00 -- 7.00 -- THORACIC 13.08 (13.02-13.30) 13.10 (13.07-13.11) LUMBAR 5.92 (5.82-5.98) 5.90 (5.89-5.93) SACRAL 3.02 (3.00-4.00) 3.00 -- CAUDAL 7.51 (6.78-8.14) 7.60 (7.27-7.96)RIBS (pairs) 13.05 (13.01-13.12) 13.07 (13.04-13.09)STERNUM MANUBRIUM 1.00 -- 1.00 -- STERNAL CENTERS 4.00 (3.98-4.00) 4.00 -- XIPHOID 1.00 -- 1.00 --FORELIMB a

CARPALS 0.00 -- 0.00 -- METACARPALS 4.00 (3.98-4.00) 4.00 -- DIGITS 5.00 -- 5.00 -- PHALANGES 8.23 (7.54-8.72) 8.28 (7.98-8.57)HINDLIMB a

TARSALS 0.03 (0.00-0.11) 0.02 (0.00-0.03) METATARSALS 4.91 (4.74-5.00) 4.90 (4.80-4.97) DIGITS 5.00 -- 5.00 -- PHALANGES 6.57 (5.73-7.63) 6.75 (6.26-7.10)

a. Calculated as average per limb

FULL STUDIES DOSE-RANGE STUDIES

22

37 36 32 3029

SUMMARY OF NATURAL DELIVERY OBSERVATIONS Crl:CD(SD) RATS (STUDIES WITHOUT CULLING)

PERIOD: JANUARY 2011 - FEBRUARY 2015

RATS ASSIGNED TO NATURAL DELIVERY N 449

PREGNANT N (%) 424 (95.8)

DELIVERED LITTERS N (%) 421 (99.5)

NO. STUDIES MEAN OR % RANGE INCLUDED

DURATION OF GESTATION (DAYS) MEAN 22.5 (22.1-22.8) 19

IMPLANTATION SITES PER DELIVERED LITTER MEAN 14.5 (12.8-16.2) 19

DAMS WITH STILLBORN PUPS % 10.8 (0-29.2) 19

DAMS WITH NO LIVEBORN PUPS % 0.0 --- 19

GESTATION INDEX (NO. RATS WITH LIVEBORN/NO. PREGNANT RATS) % 99.5 (94.7-100) 19

DAMS WITH ALL PUPS DYING DAYS 1-4 POSTPARTUM % 0.6 (0-4.3) 19

DAMS WITH ALL PUPS DYING DAYS 5-21 POSTPARTUM % 0.3 (0-4.5) 14

DAMS WITH ALL PUPS DYING DAYS 5-22 POSTPARTUM % 0.0 --- 2


PUPS DELIVERED (TOTAL) MEAN 13.6 (12.3-15.3) 19

LIVEBORN MEAN 13.4 (12.3-15.1) 19 % 98.9 (97.2-100)

STILLBORN MEAN 0.1 (0-0.4) 19 % 1.0 (0-2.8)

UNKNOWN VITAL STATUS N 0.3 (0-1) 19

23

38 37 33 3130



PUPS FOUND DEAD OR PRESUMED CANNIBALIZED DAY 1 % 0.4 (0-1.2) 19

DAYS 2-4 % 1.0 (0-5.3) 18

DAYS 2-5 % 1.8 -- 1

DAYS 5-7 % 0.3 (0-0.9) 18

DAYS 6-8 % 0.0 -- 1

DAYS 8-10 % 0.0 -- 4

DAYS 8-14 % 1.0 (0-8.1) 14

DAYS 9-15 % 0.0 -- 1

DAYS 11-14 % 0.0 -- 4

DAYS 15-17 % 0.0 -- 1

DAYS 15-18 % 0.5 (0-4.2) 17

DAYS 16-22 % 0.0 -- 1

DAYS 18-21 % 0.0 -- 1

DAYS 19-21 % 0.1 (0-0.6) 17

DAYS 22-28 % 0.2 (0-0.3) 2

VIABILITY INDEX (No. Live PPD 4 / % 98.6 (93.9-100) 19 No. Live PPD 1)

LACTATION INDEX (No. Live PPD 21 / % 98.6 (89.1-100) 19 No. Live PPD 4)

24

39 38 34 3231



SURVIVING PUPS/LITTER Day 1 MEAN 13.4 (12.3-15.1) 19

Day 4 MEAN 13.2 (12.2-14.6) 18

Day 5 MEAN 13.5 -- 1

Day 7 MEAN 13.0 (9.2-14.6) 18

Day 8 MEAN 13.5 -- 1

Day 10 MEAN 12.2 (9.2-14.3) 5

Day 14 MEAN 12.8 (9.2-14.3) 17

Day 15 MEAN 13.4 (13.2-13.5) 2

Day 17 MEAN 9.2 -- 1

Day 18 MEAN 13.0 (12.2-14.3) 14

Day 21 MEAN 12.7 (9.2-14.3) 17

Day 22 MEAN 13.5 -- 1

Day 28 MEAN 12.4 (12.3-12.4) 2

25

40 39 35 3332



PERCENT MALE PUPS PER NUMBER OF PUPS SEXED

Day 1 MEAN 51.2 (46.9-55.2) 19

Day 4 MEAN 51.2 (47.0-55.2) 18

Day 5 MEAN 52.7 -- 1

Day 7 MEAN 51.2 (46.8-55.0) 18

Day 8 MEAN 52.7 -- 1

Day 10 MEAN 53.3 (50.2-55.0) 5

Day 14 MEAN 51.3 (46.9-55.0) 17

Day 15 MEAN 52.7 -- 1

Day 17 MEAN 54.7 -- 1

Day 18 MEAN 51.1 (46.7-55.0) 14

Day 21 MEAN 51.5 (46.6-55.0) 16

Day 22 MEAN 52.0 (51.3-52.7) 2

Day 28 MEAN 51.6 (50.2-52.9) 2

26

41 40 36 3433



LIVE LITTER SIZE AT WEIGHING

Day 1 MEAN 13.4 (12.3-15.0) 19

Day 4 MEAN 13.3 (12.2-14.8) 18

Day 5 MEAN 13.5 -- 1

Day 7 MEAN 13.1 (9.2-14.7) 18

Day 8 MEAN 13.5 -- 1

Day 10 MEAN 12.2 (9.2-14.3) 5

Day 14 MEAN 12.9 (9.2-14.7) 16

Day 15 MEAN 13.5 -- 1

Day 17 MEAN 9.2 -- 1

Day 18 MEAN 13.1 (12.2-14.7) 14

Day 21 MEAN 12.9 (9.2-14.7) 17

Day 22 MEAN 13.5 -- 1

Day 28 MEAN 11.4 (10.5-12.3) 2

27

42 41 37 3534



PUP WEIGHT/LITTER (GRAMS)

Day 1 MEAN 6.9 (6.2-12.5) 19

Day 4 MEAN 9.4 (8.8-10.1) 18

Day 5 MEAN 10.0 -- 1

Day 7 MEAN 13.6 (12.3-15.6) 18

Day 8 MEAN 13.8 -- 1

Day 10 MEAN 20.1 (17.9-22.2) 5

Day 14 MEAN 25.7 (20.7-30.8) 17

Day 15 MEAN 22.6 -- 1

Day 17 MEAN 37.1 -- 1

Day 18 MEAN 32.3 (29.2-35.1) 14

Day 21 MEAN 40.2 (35.7-48.1) 17

Day 22 MEAN 34.3 -- 1

Day 28 MEAN 82.0 (81.1-82.8) 2

28

43 42 38 3635

SUMMARY OF NATURAL DELIVERY OBSERVATIONS Crl:CD(SD) RATS (STUDIES WITH CULLING)

PERIOD: MARCH 2013 - FEBRUARY 2015

RATS ASSIGNED TO NATURAL DELIVERY N 91

PREGNANT N (%) 89 (98.4)

DELIVERED LITTERS N (%) 88 (99.1)

NO. STUDIESRANGE INCLUDED

DURATION OF GESTATION IN DAYS MEAN 22.4 (22.0-22.8) 5

IMPLANTATION SITES PER DELIVERED LITTER MEAN 14.2 (13.4-15.7) 5

DAMS WITH STILLBORN PUPS % 7.0 (0.0-13.0) 5

DAMS WITH NO LIVEBORN PUPS % 1.0 (0.0-4.8) 5

GESTATION INDEX (NO. RATS WITH LIVEBORN/NO. PREGNANT RATS) % 98.2 (90.9-100.0) 5



PUPS DELIVERED (TOTAL) MEAN 13.5 (12.9-14.6) 5

LIVEBORN MEAN 13.5 (12.9-14.6) 5 % 99.5 (99.0-100.0)

STILLBORN MEAN 0.0 (0.0-0.1) 5 % 0.5 (0.0-1.0)

UNKNOWN VITAL STATUS N 0.0 --- 5

29

44 43 39 3736



PUPS FOUND DEAD OR PRESUMED CANNIBALIZED

DAY 0 % 0.5 --- 1

DAY 1 % 0.1 (0.0-0.3) 4

DAYS 1-4 % 5.4 --- 1

DAYS 2-4 % 0.5 (0.0-1.1) 4

DAYS 5-7 % 0.0 --- 4

DAYS 6-8 % 0.6 --- 1

DAYS 8-10 % 0.0 --- 1

DAYS 9-11 % 0.0 --- 1

DAYS 8-14 % 0.0 --- 2

DAYS 11-14 % 0.0 --- 2

DAYS 15-17 % 0.0 --- 3

DAYS 15-18 % 0.0 --- 1

DAYS 18-21 % 0.2 (0.0-0.6) 3

DAYS 19-21 % 0.0 --- 1

DAYS 22-28 % 0.0 --- 1

VIABILITY INDEX (No. Live PPD4 / % 98.3 (94.1-100.0) 5 No. Live PPD1)

LACTATION INDEX (No. Live PPD21 / % 99.7 (99.4-100.0) 4 No. Live PPD4)

30

45 44 40 3837



SURVIVING PUPS/LITTER

Day 0 MEAN 14.6 --- 1

Day 1 MEAN 13.3 (13.1-13.5) 3

Day 2 MEAN 12.9 --- 1

Day 4 (Preculling) MEAN 13.3 (12.9-13.7) 4

Day 4 (Postculling) MEAN 7.9 (7.7-8.0) 4

Day 5 (Preculling) MEAN 12.9 -- 1

Day 5 (Postculling) MEAN 8.0 -- 1

Day 7 MEAN 7.9 (7.7-8.0) 4

Day 8 MEAN 8.0 -- 1

Day 10 MEAN 8.0 -- 1

Day 11 MEAN 8.0 -- 1

Day 14 MEAN 7.9 (7.7-8.0) 4

Day 17 MEAN 7.9 (7.7-8.0) 3

Day 18 MEAN 8.0 -- 1

Day 20 MEAN 8.0 -- 1

Day 21 MEAN 7.9 (7.7-8.0) 3

Day 28 MEAN 8.0 -- 1

31

46 45 41 3938



PERCENT MALE PUPS PER NUMBER OF PUPS SEXED

Day 0 MEAN 42.5 --- 1

Day 1 MEAN 51.4 (48.8-53.9) 3

Day 2 MEAN 46.6 --- 1



Day 5 (Preculling) MEAN 46.6 --- 1

Day 5 (Postculling) MEAN 48.3 --- 1

Day 7 MEAN 49.8 (49.1-50.0) 4

Day 8 MEAN 48.0 --- 1

Day 10 MEAN 50.0 --- 1

Day 11 MEAN 48.0 --- 1

Day 14 MEAN 49.3 (48.0-50.0) 4

Day 17 MEAN 49.0 (48.0-50.0) 3

Day 18 MEAN 50.0 --- 1

Day 20 MEAN 48.0 --- 1

Day 21 MEAN 49.7 (49.1-50.0) 3

Day 28 MEAN 50.0 --- 1

32

47 46 42 4039



LIVE LITTER SIZE AT WEIGHING

Day 0 MEAN 14.5 --- 1

Day 1 MEAN 13.2 (13.0-13.5) 3

Day 2 MEAN 12.9 --- 1





Day 7 MEAN 7.9 (7.7-8.0) 4

Day 8 MEAN 8.0 --- 1

Day 10 MEAN 8.0 --- 1

Day 11 MEAN 8.0 --- 1

Day 14 MEAN 7.9 (7.7-8.0) 4

Day 17 MEAN 7.9 (7.7-8.0) 3

Day 18 MEAN 8.0 --- 1

Day 20 MEAN 8.0 --- 1

Day 21 MEAN 7.9 (7.7-8.0) 3

Day 28 MEAN 8.0 --- 1

33

48 47 43 4140



PUP WEIGHT/LITTER (GRAMS)

Day 0 MEAN 6.6 --- 1

Day 1 MEAN 6.6 (6.4-6.8) 3

Day 2 MEAN 7.3 --- 1





Day 7 MEAN 15.5 (12.8-18.0) 4

Day 8 MEAN 17.4 --- 1

Day 10 MEAN 23.1 --- 1

Day 11 MEAN 25.5 --- 1

Day 14 MEAN 34.3 (32.7-37.4) 4

Day 17 MEAN 42.1 (40.1-44.6) 3

Day 18 MEAN 42.0 --- 1

Day 20 MEAN 49.3 --- 1

Day 21 MEAN 53.6 (51.3-57.3) 3

Day 28 MEAN 91.0 --- 1

34

49 48 44 4241

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF REPRODUCTIVE INDICES WISTAR RATS DAY 20 CAESAREAN-SECTION

PERIOD: 2003 - 2016FULL STUDIES DOSE-RANGE STUDIES

NUMBER OF STUDIES: 10 3

NUMBER OF RATS:TESTED 239 27PREGNANT 219 25FOUND DEAD 0 1ABORTED 0 0DELIVERED 1 0

NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING: 217 25




AVERAGE LITTER SIZE

AVERAGE NO. LIVE FETUSES 11.4 (10.1-13.4) 12.5 (9.8-14.6) AVERAGE NO. DEAD FETUSES 0.0 --- 0.0 (0.0-0.1)

AVERAGE NO. RESORPTIONS 0.7 (0.5-1.3) 0.7 (0.4-0.9) AVERAGE NO. EARLY RESORPTIONS 0.7 (0.5-1.3) 0.7 (0.4-0.9) AVERAGE NO. LATE RESORPTIONS 0.0 --- 0.0 ---

42






AVERAGE % DAMS WITH ALL CONCEPTUSES RESORBED 0.0 --- 0.0 ---

AVERAGE % DAMS WITH ONE OR MORE LIVE FETUSES 99.5 (95.2-100) 100.0 ---




43



NUMBER OF STUDIES: 21 10

NUMBER OF RATS:TESTED 469 65PREGNANT 438 62FOUND DEAD 1* 0ABORTED 0 0DELIVERED 4** 1**

NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING: 432 61




AVERAGE LITTER SIZE

AVERAGE NO. LIVE FETUSES 10.0 (8.0-14.6) 10.1 (6.3-13.8) AVERAGE NO. DEAD FETUSES 0.0 --- 0.0 ---

AVERAGE NO. RESORPTIONS 0.5 (0.1-1.2) 0.4 (0.2-0.9) AVERAGE NO. EARLY RESORPTIONS 0.4 (0.1-1.1) 0.4 (0.2-0.8) AVERAGE NO. LATE RESORPTIONS 0.0 (0.0-0.1) 0.1 (0.0-0.5)

* Unscheduled euthanasia** Delivered and euthanized

44






AVERAGE % DAMS WITH ALL CONCEPTUSES RESORBED 0.4 (0.0-5.6) 0.0 ---

AVERAGE % DAMS WITH ONE OR MORE LIVE FETUSES 99.7 (94.4-100.0) 100.0 ---




45

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA LITTER AND FETAL ALTERATIONS SUMMARY WISTAR RATS DAY 20 OR 21 CAESAREAN-SECTION

PERIOD: 2003 - 2014DAY 20 DAY 21

CAESAREAN-SECTION CAESAREAN-SECTION

NUMBER OF STUDIES 2 11

NUMBER OF LITTERS EVALUATED 46 226

NUMBER OF FETUSES EVALUATED (LIVE) 551 2293


LITTERS WITH FETUSES WITHANY ALTERATION OBSERVED 50.3 (28.6-72.0) 48.0 (27.8-65.2)

FETUSES WITH ANYALTERATION OBSERVED 7.6 (4.1-11.1) 7 (3.5-11.9)

% FETUSES WITH ANYALTERATION/LITTER 8.1 (4.8-11.3) 7.1 (3.4-12.3)

39

54 53 49 4746

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS WISTAR RATS DAY 20 CAESAREAN-SECTION




HEADPurple L 0 --- --- --- 1 4.00 0-1 (0-10.0)

F 0 --- --- --- 1 0.32 0-1 (0-0.8)

EYE(S)Bulge depressed L 1 0.57 0-1 (0-4.8) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---

MOUTHOral opening small L 1 0.57 0-1 (0-4.8) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---Tongue, absent L 1 0.57 0-1 (0-4.8) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---

JAWAgnathia L 1 0.57 0-1 (0-4.8) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---

BODY L 1 0.57 0-1 (0-3.7) 0 --- --- ---Umbilical hernia F 1 0.05 0-1 (0-0.3) 0 --- --- ---

FORELIMB(S)Paw: Digit absent L 1 0.57 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---

TAILThreadlike L 0 --- --- --- 1 4.00 0-1 (0-10.0)

F 0 --- --- --- 1 0.32 0-1 (0-0.8)


47

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS WISTAR RATS DAY 21 CAESAREAN-SECTION




EYE(S)Bulge depressed L 2 1.13 0-1 (0-5.0) 0 --- --- ---

F 2 0.10 0-1 (0-0.5) 0 --- --- ---

MOUTHOral opening absent L 1 0.56 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.3) 0 --- --- ---

JAWMicrognathia L 1 0.56 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.3) 0 --- --- ---

BODYUmbilical hernia L 2 0.56 0-1 (0-4.8) 0 --- --- ---

F 2 0.05 0-1 (0-0.5) 0 --- --- ---No anal opening L 1 0.56 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.3) 0 --- --- ---Gastroschisis L 1 0.56 0-1 (0-5.0) 0 --- --- ---

F 1 0.05 0-1 (0-0.5) 0 --- --- ---

HINDLIMB(S)Rotated L 3 0.91 0-1 (0-5.6) 0 --- --- ---

F 3 0.09 0-1 (0-0.6) 0 --- --- ---

TAILThreadlike L 1 0.56 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.3) 0 --- --- ---Pedunculated L 1 0.56 0-1 (0-4.5) 0 --- --- ---

F 1 0.05 0-1 (0-0.3) 0 --- --- ---Short L 1 0.56 0-1 (0-4.3) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---Constricted L 1 0.56 0-1 (0-4.3) 0 --- --- ---

F 1 0.05 0-1 (0-0.4) 0 --- --- ---


48

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF FETAL SOFT TISSUE ALTERATIONS

WISTAR RATS DAY 20 OR 21 CAESAREAN-SECTION

PERIOD: 2003 - 2016 DAY 20 DAY 21

CAESAREAN-SECTION CAESAREAN-SECTION



BRAINLateral ventricle, slight L 2 0.76 0-2 (0-8.0) 0 --- --- --- dilation F 2 0.76 0-2 (0-1.2) 0 --- --- ---

EYE(S)Retina folded L 0 --- --- --- 1 0.55 0-1 (0-4.2)

F 0 --- --- --- 1 0.08 0-1 (0-0.8)Microphthalmia L 0 --- --- --- 1 0.55 0-1 (0-5.0)

F 0 --- --- --- 1 0.08 0-1 (0-1.0)

HEARTInterventricular septal L 0 --- --- --- 1 0.55 0-1 (0-5.0) defect F 0 --- --- --- 1 0.08 0-1 (0-1.0)

VESSELSUmbilical artery descends L 1 2.22 0-1 (0-5.0) 27 14.75 0-9 (0-44.4) to left of urinary bladder F 1 0.38 0-1 (0-1.0) 39 3.14 0-13 (0-10)Persistent truncus L 0 --- --- --- 1 0.55 0-1 (0-5.0) arteriosus F 0 --- --- --- 1 0.08 0-1 (0-1.0)Aorta descends to the right, vessels arise in incorrect order, left subclavian bran- ches from left carotid and L 0 --- --- --- 1 0.55 0-1 (0-5.0) innominate artery absent F 0 --- --- --- 1 0.08 0-1 (0-1.0)

INTESTINESProtrude through L 0 --- --- --- 1 0.55 0-1 (0-4.2) umbilicus F 0 --- --- --- 1 0.08 0-1 (0-0.8)

Misposition L 0 --- --- --- 1 0.55 0-1 (0-4.8)F 0 --- --- --- 1 0.08 0-1 (0-1.0)

LIVER L 0 --- --- --- 1 0.55 0-1 (0-5.6)Discoloration F 0 --- --- --- 1 0.08 0-1 (0-0.6)

49

Misshapen L 3 1.64 0-2 (0-14.3)F 4 0.32 0-2 (0-2.5)

STOMACH L 0 --- --- --- 1 0.55 0-1 (0-4.8)Contents discolored F 0 --- --- --- 1 0.08 0-1 (0-0.6)


50

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF FETAL SKELETAL ALTERATIONS WISTAR RATS DAY 20 OR 21 CAESAREAN-SECTION

PERIOD: 2003 - 2016

DAY 20 DAY 21 CAESAREAN-SECTION CAESAREAN-SECTION


RANGE/STUDY RANGE/STUDY ALTERATION N % N % N % N %

SKULL

Parietal :Incompletely ossified L 1 2.17 0-1 (0-4.8) 75 20.44 0-11 (0-52.4)F 1 0.35 0-1 (0-0.9) 111 5.56 0-16 (0-15.7)

Interparietal :Interparietal: Incompletely ossified L 0 --- --- --- 37 10.08 0-8 (0-38.1)F 0 --- --- --- 51 2.55 0-11 (0-11.1)

Squamosal :Incompletely ossified L 0 --- --- --- 51 13.90 0-8 (0-36.4)F 0 --- --- --- 62 3.10 0-12 (0-6.5)

Zygomatic arch : Incompletely ossified L 0 --- --- --- 52 14.17 0-10 (0-47.6)F 0 --- --- --- 60 3.00 0-11 (0-10.8)

:Fused L 0 --- --- --- 4 1.09 0-2 (0-9.1) F 0 --- --- --- 5 0.25 0-2 (0-2)

Frontal :Incompletely ossified L 0 --- --- --- 14 3.81 0-4 (0-18.2)F 0 --- --- --- 16 0.80 0-6 (0-5.9)

:Holes L 0 --- --- --- 1 0.27 0-1 (0-5)F 0 --- --- --- 1 0.55 0-1 (0-1.1)

Supraoccipital :Incompletely ossified L 1 2.17 0-1 (0-4.0) 11 3.00 0-5 (0-22.7)F 1 0.35 0-1 (0-0.6) 14 0.70 0-7 (0-6.9)

Hyoid :Incompletely ossified L 0 --- --- --- 2 0.54 0-1 (0-4.8)F 0 --- --- --- 2 0.10 0-1 (0-1)

Mandible :Thickened L 0 --- --- --- 1 0.27 0-1 (0-5.6)F 0 --- --- --- 1 0.05 0-1 (0-1.1)

Parietal :Extra ossification site L 0 --- --- --- 1 0.27 0-1 (0-5.6)F 0 --- --- --- 1 0.05 0-1 (0-1.1)

:Contains a hole L 0 --- --- --- 2 0.54 0-1 (0-5)F 0 --- --- --- 2 0.10 0-1 (0-1.1)

Suture :Large L 1 2.17 0-1 (0-4.0) 2 0.54 0-1 (0-5)F 1 0.35 0-1 (0-0.6) 9 0.45 0-8 (0-8.6)


51


DAY 20 DAY 21RANGE/STUDY RANGE/STUDY

VERTEBRAE N % N % N % N %

Cervical : Arch, Reduced ventral process, 6th L 7 15.22 0-7 (0-28.0) 7 1.91 0-2 (0-10) F 9 3.11 0-9 (0-5.1) 8 0.40 0-2 (0-2.2):Arch, Misshapen L 0 --- --- --- 2 0.54 0-2 (0-9.1)

F 0 --- --- --- 2 1.05 0-2 (0-2):Arch, Incompletely ossified L 4 8.70 0-4 (0-16.0) 1 0.27 0-1 (0-4.5)

F 5 1.73 0-5 (0-2.8) 1 0.05 0-1 (0-0.8):Lateral ossification site present L 0 --- --- --- 16 4.36 0-9 (0-42.8)at 7th cervical vertebrae F 0 --- --- --- 26 1.30 0-16 (0-8.9)

Thoracic :12 present L 0 --- --- --- 1 0.27 0-1 (0-4.3)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Arch, incompletely ossified L 0 --- --- --- 1 0.27 0-1 (0-5.6)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Arch, fused L 0 --- --- --- 1 0.27 0-1 (0-5.6)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Centrum, Bipartite ossification L 1 2.17 0-1 (0-4.0) 8 2.18 0-3 (0-14.3)Previously reported as Centrum, bifid F 1 0.35 0-1 (0-0.6) 8 0.40 0-3 (0-1.7):Centrum, irregularly shaped L 0 --- --- --- 1 0.27 0-1 (0-5.0)

F 0 --- --- --- 1 0.05 0-1 (0-1.1)Lumbar :5 present L 0 --- --- --- 2 0.54 0-2 (0-8.7)

F 0 --- --- --- 2 0.10 0-2 (0-1.4):Centrum, unilateral ossification L 0 --- --- --- 1 0.27 0-1 (0-5.6)

F 0 --- --- --- 1 0.05 0-1 (0-0.7):Arch and centrum, fused L 0 --- --- --- 1 0.27 0-1 (0-5.6)

F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Vertebra, Supernumerary L 0 --- --- --- 1 0.27 0-1 (0-5.3)F 0 --- --- --- 1 0.05 0-1 (0-1.2)

Sacral :Arch, small L 0 --- --- --- 1 0.27 0-1 (0-4.3)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Centrum, Unilateral ossification L 0 --- --- --- 1 0.27 0-1 (0-4.3)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

:Arch, Irregularly shaped L 0 --- --- --- 4 1.09 0-1 (0-5.9)F 0 --- --- --- 4 0.20 0-1 (0-1.3)

Caudal :0 present L 0 --- --- --- 1 0.27 0-1 (0-4.3)F 0 --- --- --- 1 0.05 0-1 (0-0.7)

Vertebra :Supernumerary L 0 --- --- --- 1 0.27 0-1 (0-4.5)F 0 --- --- --- 1 0.05 0-1 (0-1)


52


RANGE/STUDY RANGE/STUDYRIBS N % N % N % N %

Ribs :Incomplete ossification L 2 4.35 0-2 (0-8.0) 0 --- --- ---F 2 0.69 0-2 (0-1.1) 0 --- --- ---

:Nodulated L 0 --- --- --- 63 17.17 0-8 (0-42.1)Previously reported as Thickened F 0 --- --- --- 100 5.01 0-14 (0-15.1):One or more, wavy L 8 17.39 0-4 (16.0-19.0) 28 7.63 0-5 (0-16.7)

F 12 4.15 0-12 (3.4-5.3) 35 1.75 0-9 (0-8.9):12 present L 0 --- --- --- 1 0.27 1-1 (0-4.3)

F 0 --- --- --- 1 0.05 1-1 (0-0.7):Bowed L 0 --- --- --- 1 0.27 1-1 (0-5.0)

Cervical rib F 0 --- --- --- 1 0.05 1-1 (0-0.9):Cervical rib present at L 0 --- --- --- 13 3.54 0-4 (0-21)7th cervical vertebrae F 0 --- --- --- 16 0.80 0-5 (0-5.6):Cervical rib(s) present L 1 2.17 0-1 (0-4.0) 27 7.36 0-10 (0-43.5)

F 1 0.35 0-1 (0-0.6) 37 1.85 0-15 (0-10.9):Cervical rib, Short L 0 --- --- --- 11 3.00 0-4 (0-21.1)

F 0 --- --- --- 13 0.65 0-5 (0-5.8):Cervical rib, Full L 0 --- --- --- 4 1.09 0-4 (0-21.1)

F 0 --- --- --- 4 0.20 0-4 (0-4.7)Thoracolumbar

:Thoracolumbar, Full L 0 --- --- --- 17 4.63 0-4 (0-19)Previously reported as T14, Supernumerary F 0 --- --- --- 20 1.00 0-4 (0-4):Thoracolumbar, Short L 0 --- --- --- 107 29.16 0-21 (0-100) Previously reported as T14, F 0 --- --- --- 373 18.68 0-103 (0-57.2)Less than 1/2 of the preceding rib

STERNEBRAESternebra

:Asymmetric L 6 1.63 0-2 (0-10.5)F 6 0.30 0-2 (0-2.3)

:Fused L 2 0.54 0-1 (0-5.3)F 2 0.10 0-1 (0-1.2)

:Duplicated L 1 0.27 0-1 (0-5.0)F 1 0.05 0-1 (0-0.9)

:Incompletely ossified L 4 8.70 0-4 (0-16.0) 4 1.09 0-1 (0-5.0)F 5 1.73 0-5 (0-2.8) 4 0.20 0-1 (0-5.3)

:Misshappen L 1 0.27 0-1 (0-5.3)F 1 0.05 0-1 (0-1.2)

:Small L 1 0.27 0-1 (0-5.6)F 1 0.05 0-1 (0-0.7)

:Extra point of ossification L 12 26.09 0-12 (4.8-44.0) 1 0.27 0-1 (0-4.8)F 14 4.84 0-14 (0.9-7.4) 1 0.05 0-1 (0-0.6)

Claviculae :Extra point of ossification L 1 0.27 0-1 (0-4.8)F 1 0.05 0-1 (0-0.6)

Forelimb:Phalanges, less than the expected L 32 8.72 0-5 (0-63.6) number are ossified F 64 3.20 0-6 (0-36.6)

Hindlimb: Phalanges, less than the expected L 27 7.36 0-13 (0-72.2) number are ossified F 52 2.60 0-28 (0-19.8)


53

CHARLES RIVER LABORATORIES PRECLINICAL SERVICES, PENNSYLVANIA SUMMARY OF FETAL OSSIFICATION SITE AVERAGES

WISTAR RATS DAY 20 OR 21 CAESAREAN-SECTION

PERIOD: 2003 - 2016 DAY 20 DAY 21 CAESAREAN-SECTION CAESAREAN-SECTION


FETUS/LITTER FETUS/LITTERSKELETAL AVERAGES MEAN RANGE/STUDY MEAN RANGE/STUDY

HYOID 0.97 (0.94-1.00) 1.00 --VERTEBRAE CERVICAL 7.00 -- 7.00 -- THORACIC 13.20 -- 13.52 (13.40-13.67) LUMBAR 5.79 (5.79-5.80) 5.48 (5.33-5.58) SACRAL 3.00 -- 3.09 (3.00-3.04) CAUDAL 4.91 (4.72-5.07) 7.56 (7.05-8.23)RIBS (pairs) 13.17 (13.17-13.18) 13.43 (13.33-13.58)STERNUM MANUBRIUM 1.00 -- 1.00 -- STERNAL CENTERS 3.85 (3.82-3.88) 4.00 (3.98-4.00) XIPHOID 0.99 (0.97-1.00) 1.00 --FOREPAWS a

CARPALS 0.00 -- 0.00 -- METACARPALS 3.80 (3.77-3.82) 4.00 (3.99-4.00) DIGITS 5.00 -- 5.00 -- PHALANGES 5.48 (5.38-5.57) 8.49 (8.23-8.69)HINDPAWS a

TARSALS 0.00 -- 0.56 (0.34-0.82) METATARSALS 4.01 (4.00-4.01) 4.98 (4.92-5.00) DIGITS 5.00 -- 5.00 -- PHALANGES 5.00 -- 7.66 (6.95-8.15)

a. Calculated as average per limb

54

TABLE OF CONTENTS1. Hamilton-Thorne Sperm Evaluation2.Sperm Morphology3.Male Fertility/ Male Reproductive Organ Weights 4.Female Estrous Cycling and Mating/Fertility5.DG 13 Maternal Reproductive Indices6.DG 20 Maternal Reproductive Indices7.DG 20 Fetal Gross External Alterations8.DG 21 Maternal Reproductive Indices9.DG 21 Litter and Fetal Alterations Summary10.DG 21 Fetal Gross External Alterations11.DG 21 Fetal Soft Tissue Alterations12.DG 21 Fetal Skeletal Alterations13.DG 21 Fetal Ossification Site Averages14.Natural Delivery Data15. DG 20 and 21 Maternal Reproductive Indices16. DG 20 and 21 Litter and Fetal Alterations Summary17.DG 20 and 21 Fetal Gross External Alterations18.DG 20 and 21 Fetal Soft Tissue Alterations19.DG 20 and 21 Fetal Skeletal Alterations20.DG 20 and 21 Fetal Ossification Site Averages

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