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TDMS Study 05091-01 Pathology Tables

NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08     
LAB: American Biogenics                                     DIHYDROCOUMARIN                                    DATE: 09/12/94       
EXPERIMENT: 05091 TEST: 01                                                                                     TIME: 08:31:40       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                   PAGE:       1        
CONT: NO1-ES-45039          ROUTE: GAVAGE                                                                      NTP C#: 55890B       
PATHOLOGIST: R. DAHLGREN                     S. EUSTIS                                                         CAS: 119-84-6        
------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
               REASONS FOR REMOVAL:    ALL                                                                                          
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
               REMOVAL DATE RANGE:     ALL                                                                                          
                                                                                                                                    
               TREATMENT GROUPS:       INCLUDE ALL                                                                                  
NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08    
LAB: American Biogenics                                     DIHYDROCOUMARIN                                    DATE: 09/12/94      
EXPERIMENT: 05091 TEST: 01                                                                                     TIME: 08:31:40      
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                       
CONT: NO1-ES-45039          ROUTE: GAVAGE                                                                      NTP C#: 55890B      
PATHOLOGIST: R. DAHLGREN                     S. EUSTIS                                                         CAS: 119-84-6       
 
 
 
 
 
                                                    RATS(FISCHER344)
                                              ----------------------------
             FOR ALL DOSES THE TUMOR RATES IN THE FOLLOWING TISSUES/ORGANS ARE BASED ON NUMBER OF TISSUES EXAMINED.
             IN OTHER TISSUES/ORGANS, RATES ARE BASED ON NUMBER OF ANIMALS NECROPSIED.
 
 
                                                    ----------------
 
                                                    Adrenal Gland
                                                    Bone Marrow
                                                    Brain
                                                    Clitoral Gland
                                                    Epididymis
                                                    Heart
                                                    Islets, Pancreatic
                                                    Kidney
                                                    Liver
                                                    Lung
                                                    Nose
                                                    Ovary
                                                    Pancreas
                                                    Parathyroid Gland
                                                    Pituitary Gland
                                                    Preputial Gland
                                                    Prostate
                                                    Salivary Glands
                                                    Spleen
                                                    Testes
                                                    Thymus
                                                    Thyroid Gland
                                                    Urinary Bladder
NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08     
LAB: American Biogenics                                     DIHYDROCOUMARIN                                    DATE: 09/12/94       
EXPERIMENT: 05091 TEST: 01                                                                                     TIME: 08:31:40       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                        
CONT: NO1-ES-45039          ROUTE: GAVAGE                                                                      NTP C#: 55890B       
PATHOLOGIST: R. DAHLGREN                     S. EUSTIS                                                         CAS: 119-84-6        
 
 
 
 
 
                                     SUMMARY OF STATISTICALLY SIGNIFICANT (P<=.05) RESULTS
                                        IN THE ANALYSIS OF THE STUDY OF DIHYDROCOUMARIN
 
              ====================================================================================================
 
                                                           MALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Clitoral/Preputial Gland      Adenoma
                                                           Carcinoma
                                                           Carcinoma or Adenoma
                             Pituitary Gland: Pars Distalis or Unspecified Site
                                                           Adenoma
                             Skin                          Basal Cell Adenoma
                                                           Fibroma
                                                           Keratoacanthoma
                             Testes                        Adenoma
                             All Organs                    Benign Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
 
                                                           FEMALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Adrenal Medulla               Pheochromocytoma Benign
                                                           Pheochromocytoma: Benign, Complex, Malignant, NOS
                             Mammary Gland                 Fibroadenoma
                                                           Fibroma, Fibroadenoma or Adenoma
                                                           Fibroma, Fibroadenoma, Carcinoma, or Adenoma
                             Pituitary Gland: Pars Distalis or Unspecified Site
                                                           Adenoma
                             Skin                          Fibroma
                                                           Squamous Cell Papilloma
                             Stomach, Forestomach          Squamous Cell Carcinoma or Papilloma Squamous
                             All Organs                    Benign Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   1
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma Benign                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 17/89 (19%)  10/59 (17%)  12/59 (20%)  17/130 (13%)|  1/60 (2%)    7/58 (12%)   6/59 (10%)   4/59 (7%)  |
|ADJUSTED (b)           |  52.5%        48.2%        55.3%        57.9%      |   3.0%        31.0%        17.2%        16.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           | 13/28 (46%)   4/13 (31%)   2/8 (25%)    5/12 (42%) |  0/31 (0%)    6/21 (29%)   3/26 (12%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   634          668          615          529       |   716          710          580          717       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.080      P=0.474      P=0.123      P=0.110    |  P=0.234      P=0.009 **   P=0.052      P=0.105    |
|INCIDENTAL TUMOR       |  P=0.335N     P=0.273N     P=0.351N     P=0.408N   |  P=0.308      P=0.013 *    P=0.109      P=0.097    |
|LOGISTIC REGRESSION    |  P=0.394N     P=0.370N     P=0.457N     P=0.357N   |  P=0.259      P=0.012 *    P=0.057      P=0.109    |
|COCHRAN-ARMITAGE       |  P=0.130N                                          |  P=0.335                                           |
|FISHER EXACT           |               P=0.458N     P=0.507      P=0.154N   |               P=0.027 *    P=0.054      P=0.177    |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma: Benign, Complex, Malignant, NOS                                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 18/89 (20%)  11/59 (19%)  12/59 (20%)  17/130 (13%)|  2/60 (3%)    7/58 (12%)   6/59 (10%)   4/59 (7%)  |
|ADJUSTED (b)           |  53.8%        50.9%        55.3%        57.9%      |   6.2%        31.0%        17.2%        16.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           | 13/28 (46%)   4/13 (31%)   2/8 (25%)    5/12 (42%) |  1/31 (3%)    6/21 (29%)   3/26 (12%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   634          668          615          529       |   716          710          580          717       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.127      P=0.443      P=0.180      P=0.164    |  P=0.329      P=0.024 *    P=0.115      P=0.213    |
|INCIDENTAL TUMOR       |  P=0.207N     P=0.238N     P=0.228N     P=0.276N   |  P=0.413      P=0.035 *    P=0.211      P=0.204    |
|LOGISTIC REGRESSION    |  P=0.283N     P=0.378N     P=0.357N     P=0.265N   |  P=0.360      P=0.032 *    P=0.129      P=0.224    |
|COCHRAN-ARMITAGE       |  P=0.083N                                          |  P=0.447                                           |
|FISHER EXACT           |               P=0.493N     P=0.573      P=0.110N   |               P=0.074      P=0.131      P=0.332    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   2
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  8/86 (9%)    1/59 (2%)    1/58 (2%)    1/129 (1%) |  3/57 (5%)    1/57 (2%)    2/60 (3%)    1/59 (2%)  |
|ADJUSTED (b)           |  27.3%         7.7%        12.5%         3.3%      |   9.0%         2.9%         7.2%         4.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  7/28 (25%)   1/13 (8%)    1/8 (13%)    0/12 (0%)  |  2/30 (7%)    0/20 (0%)    1/26 (4%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   704          729 (T)      729 (T)      681       |   652          657          717          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.082N     P=0.141N     P=0.298N     P=0.133N   |  P=0.346N     P=0.409N     P=0.550N     P=0.407N   |
|INCIDENTAL TUMOR       |  P=0.038N*    P=0.089N     P=0.179N     P=0.034N*  |  P=0.338N     P=0.287N     P=0.452N     P=0.392N   |
|LOGISTIC REGRESSION    |  P=0.027N*    P=0.082N     P=0.140N     P=0.034N*  |  P=0.301N     P=0.343N     P=0.484N     P=0.352N   |
|COCHRAN-ARMITAGE       |  P=0.003N**                                        |  P=0.266N                                          |
|FISHER EXACT           |               P=0.059N     P=0.062N     P=0.003N** |               P=0.309N     P=0.476N     P=0.296N   |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  4/86 (5%)    3/59 (5%)    0/58 (0%)    1/129 (1%) |  2/57 (4%)    4/57 (7%)    0/60 (0%)    1/59 (2%)  |
|ADJUSTED (b)           |  10.5%         7.7%         0.0%         1.5%      |   5.3%        16.5%         0.0%         3.3%      |
|INTERIM SACRIFICE 1 (c)|  1/19 (5%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  1/30 (3%)    2/20 (10%)   0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   275 (I)      576          ---          577       |   506          682          ---          678       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.074N     P=0.481      P=0.291N     P=0.238N   |  P=0.249N     P=0.217      P=0.253N     P=0.562N   |
|INCIDENTAL TUMOR       |  P=0.025N*    P=0.469N     P=0.197N     P=0.103N   |  P=0.237N     P=0.330      P=0.355N     P=0.525N   |
|LOGISTIC REGRESSION    |  P=0.031N*    P=0.641      P=0.106N     P=0.082N   |  P=0.204N     P=0.295      P=0.230N     P=0.494N   |
|COCHRAN-ARMITAGE       |  P=0.031N*                                         |  P=0.188N                                          |
|FISHER EXACT           |               P=0.598      P=0.124N     P=0.085N   |               P=0.339      P=0.235N     P=0.487N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   3
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 12/86 (14%)   4/59 (7%)    1/58 (2%)    2/129 (2%) |  5/57 (9%)    5/57 (9%)    2/60 (3%)    2/59 (3%)  |
|ADJUSTED (b)           |  36.6%        14.8%        12.5%         4.8%      |  14.1%        19.0%         7.2%         7.5%      |
|INTERIM SACRIFICE 1 (c)|  1/19 (5%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  9/28 (32%)   1/13 (8%)    1/8 (13%)    0/12 (0%)  |  3/30 (10%)   2/20 (10%)   1/26 (4%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   275 (I)      576          729 (T)      577       |   506          657          717          678       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.014N*    P=0.313N     P=0.124N     P=0.050N*  |  P=0.171N     P=0.445      P=0.261N     P=0.322N   |
|INCIDENTAL TUMOR       |  P=0.002N**   P=0.073N     P=0.047N*    P=0.004N** |  P=0.154N     P=0.628N     P=0.243N     P=0.288N   |
|LOGISTIC REGRESSION    |  P<0.001N**   P=0.066N     P=0.003N**   P<0.001N** |  P=0.121N     P=0.568      P=0.195N     P=0.240N   |
|COCHRAN-ARMITAGE       |  P<0.001N**                                        |  P=0.102N                                          |
|FISHER EXACT           |               P=0.138N     P=0.009N**   P<0.001N** |               P=0.629N     P=0.199N     P=0.205N   |
|=================================================================================================================================|
|                                                                                                                                 |
|Islets, Pancreatic                                                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  5/88 (6%)    2/57 (4%)    4/58 (7%)    3/120 (3%) |  2/60 (3%)    0/53 (0%)    1/60 (2%)    1/58 (2%)  |
|ADJUSTED (b)           |  15.5%        11.0%        24.8%        12.8%      |   6.5%         0.0%         2.7%         4.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  4/28 (14%)   1/13 (8%)    1/8 (13%)    1/12 (8%)  |  2/31 (6%)    0/21 (0%)    0/26 (0%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   457 (I)      668          662          661       |   729 (T)      ---          678          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.523      P=0.541N     P=0.260      P=0.623N   |  P=0.560N     P=0.327N     P=0.544N     P=0.604N   |
|INCIDENTAL TUMOR       |  P=0.377N     P=0.483N     P=0.520      P=0.489N   |  P=0.575N     P=0.327N     P=0.510N     P=0.604N   |
|LOGISTIC REGRESSION    |  P=0.291N     P=0.331N     P=0.621N     P=0.272N   |  P=0.550N     P=0.327N     P=0.510N     P=0.604N   |
|COCHRAN-ARMITAGE       |  P=0.191N                                          |  P=0.498N                                          |
|FISHER EXACT           |               P=0.432N     P=0.512      P=0.207N   |               P=0.280N     P=0.500N     P=0.513N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   4
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Kidney: Pelvis and Transitional Epithelium                                                                                       |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/89 (0%)    0/58 (0%)    0/57 (0%)    2/130 (2%) |  0/60 (0%)    0/56 (0%)    0/59 (0%)    0/58 (0%)  |
|ADJUSTED (b)           |   0.0%         0.0%         0.0%         2.2%      |   0.0%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          ---          ---          444       |   ---          ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.102        (e)          (e)        P=0.348    |    (e)          (e)          (e)          (e)      |
|INCIDENTAL TUMOR       |  P=0.205        (e)          (e)        P=0.464    |    (e)          (e)          (e)          (e)      |
|LOGISTIC REGRESSION    |  P=0.129        (e)          (e)        P=0.325    |    (e)          (e)          (e)          (e)      |
|COCHRAN-ARMITAGE       |  P=0.113                                           |    (e)                                             |
|FISHER EXACT           |                 (e)          (e)        P=0.351    |                 (e)          (e)          (e)      |
|=================================================================================================================================|
|                                                                                                                                 |
|Kidney: Renal Tubule                                                                                                             |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/89 (0%)    1/58 (2%)    0/57 (0%)    2/130 (2%) |  1/60 (2%)    1/56 (2%)    1/59 (2%)    0/58 (0%)  |
|ADJUSTED (b)           |   0.0%         3.6%         0.0%         5.7%      |   3.2%         3.4%         3.8%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  1/31 (3%)    0/21 (0%)    1/26 (4%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          668          ---          605       |   729 (T)      710          729 (T)      ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.178      P=0.455        (e)        P=0.245    |  P=0.359N     P=0.702      P=0.723      P=0.560N   |
|INCIDENTAL TUMOR       |  P=0.374      P=0.581        (e)        P=0.556    |  P=0.369N     P=0.749      P=0.723      P=0.560N   |
|LOGISTIC REGRESSION    |  P=0.228      P=0.446        (e)        P=0.304    |  P=0.354N     P=0.718      P=0.723      P=0.560N   |
|COCHRAN-ARMITAGE       |  P=0.268                                           |  P=0.315N                                          |
|FISHER EXACT           |               P=0.395        (e)        P=0.351    |               P=0.735      P=0.748      P=0.508N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   5
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Kidney: Renal Tubule                                                                                                             |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/89 (0%)    1/58 (2%)    0/57 (0%)    2/130 (2%) |  1/60 (2%)    1/56 (2%)    2/59 (3%)    0/58 (0%)  |
|ADJUSTED (b)           |   0.0%         3.6%         0.0%         5.7%      |   3.2%         3.4%         6.1%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  1/31 (3%)    0/21 (0%)    1/26 (4%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          668          ---          605       |   729 (T)      710          624          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.178      P=0.455        (e)        P=0.245    |  P=0.420N     P=0.702      P=0.459      P=0.560N   |
|INCIDENTAL TUMOR       |  P=0.374      P=0.581        (e)        P=0.556    |  P=0.351N     P=0.749      P=0.550      P=0.560N   |
|LOGISTIC REGRESSION    |  P=0.228      P=0.446        (e)        P=0.304    |  P=0.398N     P=0.718      P=0.496      P=0.560N   |
|COCHRAN-ARMITAGE       |  P=0.268                                           |  P=0.371N                                          |
|FISHER EXACT           |               P=0.395        (e)        P=0.351    |               P=0.735      P=0.494      P=0.508N   |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Adenoma                                                                                                      |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/88 (0%)    1/57 (2%)    2/59 (3%)    3/128 (2%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    1/59 (2%)  |
|ADJUSTED (b)           |   0.0%         7.7%         6.3%        12.3%      |   0.0%         0.0%         0.0%         4.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    1/10 (10%)   0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    1/13 (8%)    0/8 (0%)     1/12 (8%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   ---          729 (T)      459 (I)      640       |   ---          ---          ---          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.053      P=0.347      P=0.137      P=0.095    |  P=0.179        (e)          (e)        P=0.440    |
|INCIDENTAL TUMOR       |  P=0.115      P=0.347      P=0.257      P=0.206    |  P=0.179        (e)          (e)        P=0.440    |
|LOGISTIC REGRESSION    |  P=0.144      P=0.347      P=0.148      P=0.155    |  P=0.179        (e)          (e)        P=0.440    |
|COCHRAN-ARMITAGE       |  P=0.187                                           |  P=0.198                                           |
|FISHER EXACT           |               P=0.393      P=0.159      P=0.206    |                 (e)          (e)        P=0.496    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   6
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Carcinoma or Hepatocellular Adenoma                                                                          |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/88 (0%)    1/57 (2%)    3/59 (5%)    3/128 (2%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    1/59 (2%)  |
|ADJUSTED (b)           |   0.0%         7.7%         9.4%        12.3%      |   0.0%         0.0%         0.0%         4.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    1/10 (10%)   0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    1/13 (8%)    0/8 (0%)     1/12 (8%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   ---          729 (T)      459 (I)      640       |   ---          ---          ---          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.062      P=0.347      P=0.066      P=0.095    |  P=0.179        (e)          (e)        P=0.440    |
|INCIDENTAL TUMOR       |  P=0.153      P=0.347      P=0.186      P=0.206    |  P=0.179        (e)          (e)        P=0.440    |
|LOGISTIC REGRESSION    |  P=0.159      P=0.347      P=0.072      P=0.155    |  P=0.179        (e)          (e)        P=0.440    |
|COCHRAN-ARMITAGE       |  P=0.210                                           |  P=0.198                                           |
|FISHER EXACT           |               P=0.393      P=0.063      P=0.206    |                 (e)          (e)        P=0.496    |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Carcinoma, Hepatocellular Adenoma, or Hepatoblastoma                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/88 (0%)    1/57 (2%)    3/59 (5%)    3/128 (2%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    1/59 (2%)  |
|ADJUSTED (b)           |   0.0%         7.7%         9.4%        12.3%      |   0.0%         0.0%         0.0%         4.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    1/10 (10%)   0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    1/13 (8%)    0/8 (0%)     1/12 (8%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   ---          729 (T)      459 (I)      640       |   ---          ---          ---          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.062      P=0.347      P=0.066      P=0.095    |  P=0.179        (e)          (e)        P=0.440    |
|INCIDENTAL TUMOR       |  P=0.153      P=0.347      P=0.186      P=0.206    |  P=0.179        (e)          (e)        P=0.440    |
|LOGISTIC REGRESSION    |  P=0.159      P=0.347      P=0.072      P=0.155    |  P=0.179        (e)          (e)        P=0.440    |
|COCHRAN-ARMITAGE       |  P=0.210                                           |  P=0.198                                           |
|FISHER EXACT           |               P=0.393      P=0.063      P=0.206    |                 (e)          (e)        P=0.496    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   7
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Adenoma                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  3/89 (3%)    1/60 (2%)    1/60 (2%)    1/130 (1%) |  1/60 (2%)    0/58 (0%)    0/60 (0%)    0/59 (0%)  |
|ADJUSTED (b)           |   8.5%         7.7%        12.5%         2.3%      |   3.2%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    1/13 (8%)    1/8 (13%)    0/12 (0%)  |  1/31 (3%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   457 (I)      729 (T)      729 (T)      661       |   729 (T)      ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.413N     P=0.588N     P=0.718N     P=0.432N   |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|INCIDENTAL TUMOR       |  P=0.363N     P=0.588N     P=0.718N     P=0.335N   |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|LOGISTIC REGRESSION    |  P=0.166N     P=0.391N     P=0.365N     P=0.199N   |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|COCHRAN-ARMITAGE       |  P=0.138N                                          |  P=0.306N                                          |
|FISHER EXACT           |               P=0.469N     P=0.469N     P=0.185N   |               P=0.508N     P=0.500N     P=0.504N   |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Carcinoma or Alveolar/Bronchiolar Adenoma                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  3/89 (3%)    1/60 (2%)    1/60 (2%)    1/130 (1%) |  1/60 (2%)    0/58 (0%)    1/60 (2%)    0/59 (0%)  |
|ADJUSTED (b)           |   8.5%         7.7%        12.5%         2.3%      |   3.2%         0.0%         3.8%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    1/13 (8%)    1/8 (13%)    0/12 (0%)  |  1/31 (3%)    0/21 (0%)    1/26 (4%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   457 (I)      729 (T)      729 (T)      661       |   729 (T)      ---          729 (T)      ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.413N     P=0.588N     P=0.718N     P=0.432N   |  P=0.449N     P=0.578N     P=0.723      P=0.560N   |
|INCIDENTAL TUMOR       |  P=0.363N     P=0.588N     P=0.718N     P=0.335N   |  P=0.449N     P=0.578N     P=0.723      P=0.560N   |
|LOGISTIC REGRESSION    |  P=0.166N     P=0.391N     P=0.365N     P=0.199N   |  P=0.449N     P=0.578N     P=0.723      P=0.560N   |
|COCHRAN-ARMITAGE       |  P=0.138N                                          |  P=0.406N                                          |
|FISHER EXACT           |               P=0.469N     P=0.469N     P=0.185N   |               P=0.508N     P=0.752N     P=0.504N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   8
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroadenoma                                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  3/90 (3%)    2/60 (3%)    0/60 (0%)    2/130 (2%) | 15/60 (25%)  10/58 (17%)  22/60 (37%)   6/60 (10%) |
|ADJUSTED (b)           |   9.3%         5.7%         0.0%        16.7%      |  39.5%        36.7%        59.2%        19.5%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  1/10 (10%)   1/7 (14%)    0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    0/13 (0%)    0/8 (0%)     2/12 (17%) |  9/31 (29%)   5/21 (24%)  12/26 (46%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   619          584          ---          729 (T)   |   462 (I)      462 (I)      611          521       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.503N     P=0.661      P=0.291N     P=0.601    |  P=0.198N     P=0.516N     P=0.066      P=0.103N   |
|INCIDENTAL TUMOR       |  P=0.369N     P=0.361N     P=0.197N     P=0.691N   |  P=0.089N     P=0.303N     P=0.182      P=0.041N*  |
|LOGISTIC REGRESSION    |  P=0.275N     P=0.612N     P=0.157N     P=0.516N   |  P=0.110N     P=0.302N     P=0.104      P=0.047N*  |
|COCHRAN-ARMITAGE       |  P=0.216N                                          |  P=0.070N                                          |
|FISHER EXACT           |               P=0.685N     P=0.213N     P=0.332N   |               P=0.210N     P=0.118      P=0.026N*  |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma or Adenoma                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  4/90 (4%)    2/60 (3%)    0/60 (0%)    2/130 (2%) | 15/60 (25%)  10/58 (17%)  22/60 (37%)   6/60 (10%) |
|ADJUSTED (b)           |  12.7%         5.7%         0.0%        16.7%      |  39.5%        36.7%        59.2%        19.5%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  1/10 (10%)   1/7 (14%)    0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  3/28 (11%)   0/13 (0%)    0/8 (0%)     2/12 (17%) |  9/31 (29%)   5/21 (24%)  12/26 (46%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   619          584          ---          729 (T)   |   462 (I)      462 (I)      611          521       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.386N     P=0.580N     P=0.227N     P=0.657N   |  P=0.198N     P=0.516N     P=0.066      P=0.103N   |
|INCIDENTAL TUMOR       |  P=0.268N     P=0.267N     P=0.154N     P=0.568N   |  P=0.089N     P=0.303N     P=0.182      P=0.041N*  |
|LOGISTIC REGRESSION    |  P=0.167N     P=0.457N     P=0.094N     P=0.372N   |  P=0.110N     P=0.302N     P=0.104      P=0.047N*  |
|COCHRAN-ARMITAGE       |  P=0.119N                                          |  P=0.070N                                          |
|FISHER EXACT           |               P=0.544N     P=0.126N     P=0.189N   |               P=0.210N     P=0.118      P=0.026N*  |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE   9
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma, Carcinoma, or Adenoma                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  4/90 (4%)    2/60 (3%)    0/60 (0%)    2/130 (2%) | 15/60 (25%)  10/58 (17%)  22/60 (37%)   6/60 (10%) |
|ADJUSTED (b)           |  12.7%         5.7%         0.0%        16.7%      |  39.5%        36.7%        59.2%        19.5%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  1/10 (10%)   1/7 (14%)    0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  3/28 (11%)   0/13 (0%)    0/8 (0%)     2/12 (17%) |  9/31 (29%)   5/21 (24%)  12/26 (46%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   619          584          ---          729 (T)   |   462 (I)      462 (I)      611          521       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.386N     P=0.580N     P=0.227N     P=0.657N   |  P=0.198N     P=0.516N     P=0.066      P=0.103N   |
|INCIDENTAL TUMOR       |  P=0.268N     P=0.267N     P=0.154N     P=0.568N   |  P=0.089N     P=0.303N     P=0.182      P=0.041N*  |
|LOGISTIC REGRESSION    |  P=0.167N     P=0.457N     P=0.094N     P=0.372N   |  P=0.110N     P=0.302N     P=0.104      P=0.047N*  |
|COCHRAN-ARMITAGE       |  P=0.119N                                          |  P=0.070N                                          |
|FISHER EXACT           |               P=0.544N     P=0.126N     P=0.189N   |               P=0.210N     P=0.118      P=0.026N*  |
|=================================================================================================================================|
|                                                                                                                                 |
|Pancreas                                                                                                                         |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  2/88 (2%)    5/57 (9%)    4/58 (7%)    2/117 (2%) |  0/58 (0%)    0/53 (0%)    1/59 (2%)    0/58 (0%)  |
|ADJUSTED (b)           |   7.1%        24.2%        18.7%         6.5%      |   0.0%         0.0%         3.8%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    2/13 (15%)   0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    1/26 (4%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   729 (T)      549          662          537       |   ---          ---          729 (T)      ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.565      P=0.063      P=0.102      P=0.543    |  P=0.665        (e)        P=0.465        (e)      |
|INCIDENTAL TUMOR       |  P=0.218N     P=0.144      P=0.408      P=0.691N   |  P=0.665        (e)        P=0.465        (e)      |
|LOGISTIC REGRESSION    |  P=0.325N     P=0.119      P=0.220      P=0.641N   |  P=0.665        (e)        P=0.465        (e)      |
|COCHRAN-ARMITAGE       |  P=0.245N                                          |  P=0.697                                           |
|FISHER EXACT           |               P=0.084      P=0.171      P=0.576N   |                 (e)        P=0.504        (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  10
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Pituitary Gland: Pars Distalis or Unspecified Site                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 26/88 (30%)  21/57 (37%)  14/56 (25%)  18/122 (15%)| 36/59 (61%)  21/55 (38%)  28/59 (47%)  20/59 (34%) |
|ADJUSTED (b)           |  64.4%        74.2%        51.6%        65.8%      |  75.3%        68.7%        68.1%        56.0%      |
|INTERIM SACRIFICE 1 (c)|  1/19 (5%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    1/10 (10%)   1/10 (10%)   0/20 (0%)  |  5/10 (50%)   0/7 (0%)     1/10 (10%)   1/9 (11%)  |
|TERMINAL (d)           | 15/28 (54%)   7/13 (54%)   1/8 (13%)    5/11 (45%) | 20/31 (65%)  12/21 (57%)  14/26 (54%)  10/23 (43%) |
|FIRST INCIDENCE (DAYS) |   275 (I)      458 (I)      459 (I)      483       |   385          471          462 (I)      455       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.410N     P=0.098      P=0.447      P=0.532    |  P=0.099N     P=0.194N     P=0.279N     P=0.077N   |
|INCIDENTAL TUMOR       |  P=0.002N**   P=0.425N     P=0.045N*    P=0.012N*  |  P=0.016N*    P=0.027N*    P=0.117N     P=0.004N** |
|LOGISTIC REGRESSION    |  P=0.002N**   P=0.533      P=0.078N     P=0.010N** |  P=0.015N*    P=0.017N*    P=0.094N     P=0.005N** |
|COCHRAN-ARMITAGE       |  P=0.001N**                                        |  P=0.008N**                                        |
|FISHER EXACT           |               P=0.231      P=0.346N     P=0.008N** |               P=0.012N*    P=0.098N     P=0.003N** |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Basal Cell Adenoma                                                                                                          |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/90 (0%)    0/60 (0%)    0/60 (0%)    3/130 (2%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    0/60 (0%)  |
|ADJUSTED (b)           |   0.0%         0.0%         0.0%        12.6%      |   0.0%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          ---          ---          661       |   ---          ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.012 *      (e)          (e)        P=0.083    |    (e)          (e)          (e)          (e)      |
|INCIDENTAL TUMOR       |  P=0.058        (e)          (e)        P=0.381    |    (e)          (e)          (e)          (e)      |
|LOGISTIC REGRESSION    |  P=0.022 *      (e)          (e)        P=0.136    |    (e)          (e)          (e)          (e)      |
|COCHRAN-ARMITAGE       |  P=0.046 *                                         |    (e)                                             |
|FISHER EXACT           |                 (e)          (e)        P=0.204    |                 (e)          (e)          (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  11
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Fibroma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  1/90 (1%)    4/60 (7%)    0/60 (0%)    3/130 (2%) |  0/60 (0%)    0/58 (0%)    1/60 (2%)    2/60 (3%)  |
|ADJUSTED (b)           |   3.6%        22.1%         0.0%        16.1%      |   0.0%         0.0%         3.8%         8.3%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  1/28 (4%)    2/13 (15%)   0/8 (0%)     1/12 (8%)  |  0/31 (0%)    0/21 (0%)    1/26 (4%)    1/23 (4%)  |
|FIRST INCIDENCE (DAYS) |   729 (T)      599          ---          661       |   ---          ---          729 (T)      717       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.243      P=0.049 *    P=0.748N     P=0.148    |  P=0.055        (e)        P=0.465      P=0.178    |
|INCIDENTAL TUMOR       |  P=0.455      P=0.119      P=0.748N     P=0.332    |  P=0.045 *      (e)        P=0.465      P=0.171    |
|LOGISTIC REGRESSION    |  P=0.469      P=0.101      P=0.748N     P=0.271    |  P=0.052        (e)        P=0.465      P=0.184    |
|COCHRAN-ARMITAGE       |  P=0.545N                                          |  P=0.072                                           |
|FISHER EXACT           |               P=0.083      P=0.600N     P=0.459    |                 (e)        P=0.500      P=0.248    |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Keratoacanthoma                                                                                                             |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  3/90 (3%)    3/60 (5%)    2/60 (3%)    0/130 (0%) |  0/60 (0%)    0/58 (0%)    2/60 (3%)    0/60 (0%)  |
|ADJUSTED (b)           |   8.5%        11.5%        16.0%         0.0%      |   0.0%         0.0%         7.7%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    0/13 (0%)    1/8 (13%)    0/12 (0%)  |  0/31 (0%)    0/21 (0%)    2/26 (8%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   457 (I)      634          684          ---       |   ---          ---          729 (T)      ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.136N     P=0.408      P=0.477      P=0.225N   |  P=0.551        (e)        P=0.200        (e)      |
|INCIDENTAL TUMOR       |  P=0.046N*    P=0.642      P=0.587      P=0.225N   |  P=0.551        (e)        P=0.200        (e)      |
|LOGISTIC REGRESSION    |  P=0.041N*    P=0.542      P=0.581N     P=0.072N   |  P=0.551        (e)        P=0.200        (e)      |
|COCHRAN-ARMITAGE       |  P=0.034N*                                         |  P=0.597                                           |
|FISHER EXACT           |               P=0.456      P=0.685N     P=0.067N   |                 (e)        P=0.248        (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  12
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Squamous Cell Papilloma                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  2/90 (2%)    1/60 (2%)    1/60 (2%)    1/130 (1%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    2/60 (3%)  |
|ADJUSTED (b)           |   5.4%         4.3%         6.7%         8.3%      |   0.0%         0.0%         0.0%         8.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     1/12 (8%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    2/23 (9%)  |
|FIRST INCIDENCE (DAYS) |   655          681          709          729 (T)   |   ---          ---          ---          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.455N     P=0.586N     P=0.587N     P=0.543N   |  P=0.037 *      (e)          (e)        P=0.175    |
|INCIDENTAL TUMOR       |  P=0.205N     P=0.357N     P=0.219N     P=0.335N   |  P=0.037 *      (e)          (e)        P=0.175    |
|LOGISTIC REGRESSION    |  P=0.334N     P=0.587N     P=0.561N     P=0.432N   |  P=0.037 *      (e)          (e)        P=0.175    |
|COCHRAN-ARMITAGE       |  P=0.267N                                          |  P=0.048 *                                         |
|FISHER EXACT           |               P=0.649N     P=0.649N     P=0.365N   |                 (e)          (e)        P=0.248    |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Trichoepithelioma, Kertatocanthoma, Squamous Cell Carcinoma,                                                                |
|     Basal Cell Carcinoma or Adenoma, Papilloma Squamous, or Papilloma                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  5/90 (6%)    3/60 (5%)    3/60 (5%)    4/130 (3%) |  0/60 (0%)    0/58 (0%)    2/60 (3%)    2/60 (3%)  |
|ADJUSTED (b)           |  13.5%        11.5%        21.6%        19.9%      |   0.0%         0.0%         7.7%         8.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  1/19 (5%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    0/13 (0%)    1/8 (13%)    1/12 (8%)  |  0/31 (0%)    0/21 (0%)    2/26 (8%)    2/23 (9%)  |
|FIRST INCIDENCE (DAYS) |   457 (I)      634          684          661       |   ---          ---          729 (T)      729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.525      P=0.607N     P=0.578      P=0.595    |  P=0.064        (e)        P=0.200      P=0.175    |
|INCIDENTAL TUMOR       |  P=0.210N     P=0.318N     P=0.399N     P=0.291N   |  P=0.064        (e)        P=0.200      P=0.175    |
|LOGISTIC REGRESSION    |  P=0.308N     P=0.499N     P=0.455N     P=0.353N   |  P=0.064        (e)        P=0.200      P=0.175    |
|COCHRAN-ARMITAGE       |  P=0.219N                                          |  P=0.088                                           |
|FISHER EXACT           |               P=0.596N     P=0.596N     P=0.282N   |                 (e)        P=0.248      P=0.248    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  13
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Stomach, Forestomach                                                                                                             |
|     Squamous Cell Carcinoma or Papilloma Squamous                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/90 (0%)    0/60 (0%)    0/60 (0%)    0/130 (0%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    2/60 (3%)  |
|ADJUSTED (b)           |   0.0%         0.0%         0.0%         0.0%      |   0.0%         0.0%         0.0%         8.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    2/23 (9%)  |
|FIRST INCIDENCE (DAYS) |   ---          ---          ---          ---       |   ---          ---          ---          729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |    (e)          (e)          (e)          (e)      |  P=0.037 *      (e)          (e)        P=0.175    |
|INCIDENTAL TUMOR       |    (e)          (e)          (e)          (e)      |  P=0.037 *      (e)          (e)        P=0.175    |
|LOGISTIC REGRESSION    |    (e)          (e)          (e)          (e)      |  P=0.037 *      (e)          (e)        P=0.175    |
|COCHRAN-ARMITAGE       |    (e)                                             |  P=0.048 *                                         |
|FISHER EXACT           |                 (e)          (e)          (e)      |                 (e)          (e)        P=0.248    |
|=================================================================================================================================|
|                                                                                                                                 |
|Testes                                                                                                                           |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 56/88 (64%)  41/59 (69%)  41/59 (69%)  85/126 (67%)|                                                    |
|ADJUSTED (b)           | 100.0%        97.4%       100.0%        98.7%      |                                                    |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)| 13/19 (68%)   2/10 (20%)   2/10 (20%)  11/20 (55%) |                                                    |
|TERMINAL (d)           | 28/28 (100%) 12/13 (92%)   8/8 (100%)  11/12 (92%) |                                                    |
|FIRST INCIDENCE (DAYS) |   457 (I)      458 (I)      458 (I)      457 (I)   |                                                    |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P<0.001 **   P=0.099      P=0.016 *    P<0.001 ** |                                                    |
|INCIDENTAL TUMOR       |  P=0.157      P=0.063N     P=0.055N     P=0.554    |                                                    |
|LOGISTIC REGRESSION    |  P=0.231      P=0.050N     P=0.008N**   P=0.413N   |                                                    |
|COCHRAN-ARMITAGE       |  P=0.373                                           |                                                    |
|FISHER EXACT           |               P=0.290      P=0.290      P=0.331    |                                                    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  14
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  1/89 (1%)    1/58 (2%)    0/59 (0%)    1/116 (1%) |  1/59 (2%)    4/55 (7%)    1/59 (2%)    2/59 (3%)  |
|ADJUSTED (b)           |   2.1%         7.7%         0.0%         3.4%      |   3.2%        17.9%         1.9%         8.7%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     1/10 (10%)   0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    1/13 (8%)    0/8 (0%)     0/12 (0%)  |  1/31 (3%)    3/21 (14%)   0/26 (0%)    2/23 (9%)  |
|FIRST INCIDENCE (DAYS) |   534          729 (T)      ---          687       |   729 (T)      716          461 (I)      729 (T)   |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.640N     P=0.673      P=0.504N     P=0.728N   |  P=0.516      P=0.086      P=0.741      P=0.396    |
|INCIDENTAL TUMOR       |  P=0.516N     P=0.650      P=0.682N     P=0.545N   |  P=0.516      P=0.110      P=0.741      P=0.396    |
|LOGISTIC REGRESSION    |  P=0.535N     P=0.697      P=0.621N     P=0.708N   |  P=0.562      P=0.105      P=0.752      P=0.396    |
|COCHRAN-ARMITAGE       |  P=0.505N                                          |  P=0.586N                                          |
|FISHER EXACT           |               P=0.635      P=0.601N     P=0.681N   |               P=0.161      P=0.752N     P=0.500    |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: Follicular Cell                                                                                                   |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  1/89 (1%)    2/58 (3%)    1/59 (2%)    3/116 (3%) |  0/59 (0%)    1/55 (2%)    0/59 (0%)    0/59 (0%)  |
|ADJUSTED (b)           |   3.6%        13.5%         5.9%         5.4%      |   0.0%         4.8%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    1/20 (5%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  1/28 (4%)    1/13 (8%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    1/21 (5%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   729 (T)      721          701          457 (I)   |   ---          729 (T)      ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.167      P=0.267      P=0.544      P=0.266    |  P=0.597N     P=0.422        (e)          (e)      |
|INCIDENTAL TUMOR       |  P=0.362      P=0.375      P=0.764      P=0.428    |  P=0.597N     P=0.422        (e)          (e)      |
|LOGISTIC REGRESSION    |  P=0.341      P=0.300      P=0.680      P=0.392    |  P=0.597N     P=0.422        (e)          (e)      |
|COCHRAN-ARMITAGE       |  P=0.401                                           |  P=0.563N                                          |
|FISHER EXACT           |               P=0.343      P=0.640      P=0.416    |               P=0.482        (e)          (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  15
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: Follicular Cell                                                                                                   |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  2/89 (2%)    3/58 (5%)    1/59 (2%)    3/116 (3%) |  0/59 (0%)    1/55 (2%)    1/59 (2%)    1/59 (2%)  |
|ADJUSTED (b)           |   7.1%        20.7%         5.9%         5.4%      |   0.0%         4.8%         3.8%         3.1%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    1/20 (5%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    2/13 (15%)   0/8 (0%)     0/12 (0%)  |  0/31 (0%)    1/21 (5%)    1/26 (4%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   729 (T)      721          701          457 (I)   |   ---          729 (T)      729 (T)      639       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.298      P=0.196      P=0.651      P=0.386    |  P=0.334      P=0.422      P=0.465      P=0.451    |
|INCIDENTAL TUMOR       |  P=0.512      P=0.270      P=0.677N     P=0.553    |  P=0.428      P=0.422      P=0.465      P=0.701    |
|LOGISTIC REGRESSION    |  P=0.575      P=0.231      P=0.686N     P=0.593    |  P=0.359      P=0.422      P=0.465      P=0.496    |
|COCHRAN-ARMITAGE       |  P=0.509N                                          |  P=0.391                                           |
|FISHER EXACT           |               P=0.306      P=0.651N     P=0.623    |               P=0.482      P=0.500      P=0.500    |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Polyp Stromal                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    | 11/60 (18%)  13/58 (22%)   9/60 (15%)   8/60 (13%) |
|ADJUSTED (b)           |                                                    |  31.6%        42.9%        25.9%        26.4%      |
|INTERIM SACRIFICE 1 (c)|                                                    |                                                    |
|INTERIM SACRIFICE 2 (c)|                                                    |  2/10 (20%)   2/7 (29%)    3/10 (30%)   0/9 (0%)   |
|TERMINAL (d)           |                                                    |  9/31 (29%)   7/21 (33%)   5/26 (19%)   4/23 (17%) |
|FIRST INCIDENCE (DAYS) |                                                    |   461 (I)      461 (I)      461 (I)      504       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |  P=0.311N     P=0.118      P=0.528N     P=0.536N   |
|INCIDENTAL TUMOR       |                                                    |  P=0.257N     P=0.151      P=0.510N     P=0.409N   |
|LOGISTIC REGRESSION    |                                                    |  P=0.206N     P=0.304      P=0.462N     P=0.394N   |
|COCHRAN-ARMITAGE       |                                                    |  P=0.177N                                          |
|FISHER EXACT           |                                                    |               P=0.374      P=0.404N     P=0.309N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  16
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Sarcoma Stromal or Polyp Stromal                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    | 11/60 (18%)  13/58 (22%)   9/60 (15%)   9/60 (15%) |
|ADJUSTED (b)           |                                                    |  31.6%        42.9%        25.9%        27.7%      |
|INTERIM SACRIFICE 1 (c)|                                                    |                                                    |
|INTERIM SACRIFICE 2 (c)|                                                    |  2/10 (20%)   2/7 (29%)    3/10 (30%)   0/9 (0%)   |
|TERMINAL (d)           |                                                    |  9/31 (29%)   7/21 (33%)   5/26 (19%)   4/23 (17%) |
|FIRST INCIDENCE (DAYS) |                                                    |   461 (I)      461 (I)      461 (I)      455       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |  P=0.409N     P=0.118      P=0.528N     P=0.561    |
|INCIDENTAL TUMOR       |                                                    |  P=0.344N     P=0.151      P=0.510N     P=0.494N   |
|LOGISTIC REGRESSION    |                                                    |  P=0.284N     P=0.304      P=0.462N     P=0.477N   |
|COCHRAN-ARMITAGE       |                                                    |  P=0.254N                                          |
|FISHER EXACT           |                                                    |               P=0.374      P=0.404N     P=0.404N   |
|=================================================================================================================================|
|                                                                                                                                 |
|Vagina                                                                                                                           |
|     Leiomyosarcoma                                                                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    |  0/60 (0%)    2/58 (3%)    0/60 (0%)    0/60 (0%)  |
|ADJUSTED (b)           |                                                    |   0.0%         5.1%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|                                                    |                                                    |
|INTERIM SACRIFICE 2 (c)|                                                    |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |                                                    |  0/31 (0%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |                                                    |   ---          508          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |  P=0.428N     P=0.218        (e)          (e)      |
|INCIDENTAL TUMOR       |                                                    |  P=0.413N     P=0.290        (e)          (e)      |
|LOGISTIC REGRESSION    |                                                    |  P=0.392N     P=0.247        (e)          (e)      |
|COCHRAN-ARMITAGE       |                                                    |  P=0.403N                                          |
|FISHER EXACT           |                                                    |               P=0.239        (e)          (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  17
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Leukemia: Lymphocytic, Monocytic, Mononuclear,                                                                              |
|     or Undifferentiated                                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 10/90 (11%)   5/60 (8%)    8/60 (13%)  12/130 (9%) | 10/60 (17%)  10/58 (17%)  12/60 (20%)  12/60 (20%) |
|ADJUSTED (b)           |  25.5%        21.2%        46.0%        44.1%      |  25.0%        27.0%        30.3%        34.9%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  2/28 (7%)    1/13 (8%)    3/8 (38%)    4/12 (33%) |  4/31 (13%)   2/21 (10%)   3/26 (12%)   3/23 (13%) |
|FIRST INCIDENCE (DAYS) |   526          550          603          604       |   589          357          580          531       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.159      P=0.388N     P=0.382      P=0.286    |  P=0.206      P=0.397      P=0.353      P=0.217    |
|INCIDENTAL TUMOR       |  P=0.394N     P=0.053N     P=0.281N     P=0.191N   |  P=0.447      P=0.401N     P=0.514N     P=0.383    |
|LOGISTIC REGRESSION    |  P=0.298N     P=0.094N     P=0.238N     P=0.185N   |  P=0.431      P=0.535      P=0.524N     P=0.464    |
|COCHRAN-ARMITAGE       |  P=0.413N                                          |  P=0.338                                           |
|FISHER EXACT           |               P=0.397N     P=0.434      P=0.406N   |               P=0.564      P=0.407      P=0.407    |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant Lymphoma And Histiocytic Sarcoma                                                                                  |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/90 (0%)    2/60 (3%)    0/60 (0%)    0/130 (0%) |  1/60 (2%)    0/58 (0%)    0/60 (0%)    0/60 (0%)  |
|ADJUSTED (b)           |   0.0%         4.9%         0.0%         0.0%      |   3.2%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  1/31 (3%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          462          ---          ---       |   729 (T)      ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.309N     P=0.213        (e)          (e)      |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|INCIDENTAL TUMOR       |  P=0.199N     P=0.316        (e)          (e)      |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|LOGISTIC REGRESSION    |  P=0.315N     P=0.126        (e)          (e)      |  P=0.335N     P=0.578N     P=0.535N     P=0.560N   |
|COCHRAN-ARMITAGE       |  P=0.317N                                          |  P=0.305N                                          |
|FISHER EXACT           |               P=0.158        (e)          (e)      |               P=0.508N     P=0.500N     P=0.500N   |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  18
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant Lymphoma: Histiocytic, Lymphocytic, Mixed,                                                                        |
|     NOS, or Undifferentiated Cell Type                                                                                          |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/90 (0%)    2/60 (3%)    0/60 (0%)    0/130 (0%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    0/60 (0%)  |
|ADJUSTED (b)           |   0.0%         4.9%         0.0%         0.0%      |   0.0%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          462          ---          ---       |   ---          ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.309N     P=0.213        (e)          (e)      |    (e)          (e)          (e)          (e)      |
|INCIDENTAL TUMOR       |  P=0.199N     P=0.316        (e)          (e)      |    (e)          (e)          (e)          (e)      |
|LOGISTIC REGRESSION    |  P=0.315N     P=0.126        (e)          (e)      |    (e)          (e)          (e)          (e)      |
|COCHRAN-ARMITAGE       |  P=0.317N                                          |    (e)                                             |
|FISHER EXACT           |               P=0.158        (e)          (e)      |                 (e)          (e)          (e)      |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Mesothelioma Benign, Malignant, NOS                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |  0/90 (0%)    2/60 (3%)    1/60 (2%)    0/130 (0%) |  0/60 (0%)    0/58 (0%)    0/60 (0%)    0/60 (0%)  |
|ADJUSTED (b)           |   0.0%         7.5%         4.5%         0.0%      |   0.0%         0.0%         0.0%         0.0%      |
|INTERIM SACRIFICE 1 (c)|  0/19 (0%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  0/28 (0%)    0/13 (0%)    0/8 (0%)     0/12 (0%)  |  0/31 (0%)    0/21 (0%)    0/26 (0%)    0/23 (0%)  |
|FIRST INCIDENCE (DAYS) |   ---          556          694          ---       |   ---          ---          ---          ---       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.459N     P=0.177      P=0.425        (e)      |    (e)          (e)          (e)          (e)      |
|INCIDENTAL TUMOR       |  P=0.202N     P=0.402      P=0.669        (e)      |    (e)          (e)          (e)          (e)      |
|LOGISTIC REGRESSION    |  P=0.363N     P=0.178      P=0.458        (e)      |    (e)          (e)          (e)          (e)      |
|COCHRAN-ARMITAGE       |  P=0.341N                                          |    (e)                                             |
|FISHER EXACT           |               P=0.158      P=0.400        (e)      |                 (e)          (e)          (e)      |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  19
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Benign Tumors                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 64/90 (71%)  48/60 (80%)  50/60 (83%)  90/130 (69%)| 46/60 (77%)  38/58 (66%)  50/60 (83%)  32/60 (53%) |
|ADJUSTED (b)           | 100.0%        97.9%       100.0%       100.0%      |  93.6%        94.8%        96.0%        85.1%      |
|INTERIM SACRIFICE 1 (c)|  1/19 (5%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)| 15/19 (79%)   3/10 (30%)   4/10 (40%)  11/20 (55%) |  5/10 (50%)   3/7 (43%)    5/10 (50%)   1/9 (11%)  |
|TERMINAL (d)           | 28/28 (100%) 12/13 (92%)   8/8 (100%)  12/12 (100%)| 28/31 (90%)  19/21 (90%)  24/26 (92%)  18/23 (78%) |
|FIRST INCIDENCE (DAYS) |   275 (I)      458 (I)      458 (I)      457 (I)   |   385          461 (I)      461 (I)      455       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P<0.001 **   P=0.069      P=0.007 **   P<0.001 ** |  P=0.265N     P=0.254      P=0.113      P=0.268N   |
|INCIDENTAL TUMOR       |  P=0.205N     P=0.013N*    P=0.064N     P=0.102N   |  P=0.021N*    P=0.469N     P=0.223      P=0.019N*  |
|LOGISTIC REGRESSION    |  P=0.183N     P=0.031N*    P=0.032N*    P=0.046N*  |  P=0.017N*    P=0.295N     P=0.253      P=0.018N*  |
|COCHRAN-ARMITAGE       |  P=0.232N                                          |  P=0.010N**                                        |
|FISHER EXACT           |               P=0.150      P=0.062      P=0.442N   |               P=0.128N     P=0.247      P=0.006N** |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant Tumors                                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 17/90 (19%)  12/60 (20%)  11/60 (18%)  17/130 (13%)| 15/60 (25%)  20/58 (34%)  15/60 (25%)  16/60 (27%) |
|ADJUSTED (b)           |  40.8%        39.9%        51.9%        48.7%      |  36.5%        49.8%        38.6%        42.5%      |
|INTERIM SACRIFICE 1 (c)|  1/19 (5%)    0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)|  0/19 (0%)    0/10 (0%)    0/10 (0%)    0/20 (0%)  |  0/10 (0%)    0/7 (0%)     0/10 (0%)    0/9 (0%)   |
|TERMINAL (d)           |  6/28 (21%)   2/13 (15%)   3/8 (38%)    4/12 (33%) |  7/31 (23%)   4/21 (19%)   5/26 (19%)   4/23 (17%) |
|FIRST INCIDENCE (DAYS) |   275 (I)      462          603          444       |   506          357          580          455       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P=0.403      P=0.450      P=0.430      P=0.420    |  P=0.386      P=0.083      P=0.482      P=0.255    |
|INCIDENTAL TUMOR       |  P=0.056N     P=0.104N     P=0.118N     P=0.052N   |  P=0.389N     P=0.344      P=0.387N     P=0.507    |
|LOGISTIC REGRESSION    |  P=0.154N     P=0.469N     P=0.282N     P=0.191N   |  P=0.362N     P=0.166      P=0.375N     P=0.586N   |
|COCHRAN-ARMITAGE       |  P=0.105N                                          |  P=0.464N                                          |
|FISHER EXACT           |               P=0.513      P=0.554N     P=0.163N   |               P=0.177      P=0.583N     P=0.500    |
|=================================================================================================================================|
 
         DATE: 09/12/94                     EXPERIMENT: 05091 TEST: 01                                                 PAGE  20
                             STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- DIHYDROCOUMARIN
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |   0 MG/KG      150MG/KG     300MG/KG     600MG/KG  |   VEHICLE      150MG/KG     300MG/KG     600MG/KG  |
|                       |   65 KILL                                65 STOP   |   CONTROL                                          |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant and Benign Tumors                                                                                                 |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |    #            #            #            #        |    #            #            #            #        |
|-----------            |                                                    |                                                    |
|OVERALL (a)            | 65/90 (72%)  49/60 (82%)  51/60 (85%)  93/130 (72%)| 51/60 (85%)  46/58 (79%)  53/60 (88%)  40/60 (67%) |
|ADJUSTED (b)           | 100.0%       100.0%       100.0%       100.0%      |  94.3%        95.7%        98.1%        90.5%      |
|INTERIM SACRIFICE 1 (c)|  2/19 (11%)   0/0          0/0          0/19 (0%)  |                                                    |
|INTERIM SACRIFICE 2 (c)| 15/19 (79%)   3/10 (30%)   4/10 (40%)  11/20 (55%) |  5/10 (50%)   3/7 (43%)    5/10 (50%)   1/9 (11%)  |
|TERMINAL (d)           | 28/28 (100%) 13/13 (100%)  8/8 (100%)  12/12 (100%)| 28/31 (90%)  19/21 (90%)  25/26 (96%)  19/23 (83%) |
|FIRST INCIDENCE (DAYS) |   275 (I)      458 (I)      458 (I)      444       |   385          357          461 (I)      455       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |  P<0.001 **   P=0.047 *    P=0.005 **   P<0.001 ** |  P=0.428N     P=0.133      P=0.191      P=0.528N   |
|INCIDENTAL TUMOR       |  P=0.267N     P=0.030N*    P=0.083N     P=0.124N   |  P=0.010N**   P=0.477N     P=0.458      P=0.027N*  |
|LOGISTIC REGRESSION    |  P=0.247N     P=0.031N*    P=0.046N*    P=0.112N   |  P=0.019N*    P=0.585N     P=0.424      P=0.046N*  |
|COCHRAN-ARMITAGE       |  P=0.292N                                          |  P=0.012N*                                         |
|FISHER EXACT           |               P=0.128      P=0.050 *    P=0.518N   |               P=0.286N     P=0.395      P=0.016N*  |
|=================================================================================================================================|
 
 (a)  Number of tumor-bearing animals / number of animals examined at site.
 (b)  Kaplan-Meier estimated lifetime tumor incidence after adjustment for 
      intercurrent mortality.
 (c)  Observed incidence at interim kill.
          Male interim sacrifices(days):   274  457
          Female interim sacrifices(days): 461
 (d)  Observed incidence at terminal kill.
 (f)  Beneath the control incidence are the P-values associated with the trend 
      test.  Beneath the dosed group incidence are the P-values corresponding to 
      pairwise comparisons between the controls and that dosed group.  The life
      table analysis regards tumors in animals dying  prior to terminal kill as
      being (directly or indirectly) the cause of death.  The incidental tumor 
      test regards these lesions as non-fatal.  Logistic regression is an alternative
      method for analyzing the incidence of non-fatal tumors.  The Cochran-Armitage
      and Fisher's exact tests compare directly the overall incidence rates.  
      For all tests, a negative trend is indicated by "N".
 (e)  Value of Statistic cannot be computed. 
 (I)  Interim sacrifice
 (T)  Terminal sacrifice
  #   Tumor rates based on number of animals necropsied.
 
  *   To the right of any statistical result, indicates significance at (P<=0.05).
  **  To the right of any statistical result, indicates significance at (P<=0.01).