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TR 399 Rat Pathology Tables

NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08     
LAB: Mason                                                TITANOCENE DICHLORIDE                                DATE: 09/06/94       
EXPERIMENT: 05047 TEST: 01                                                                                     TIME: 22:02:50       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                   PAGE:       1        
CONT: N01ES9561904          ROUTE: GAVAGE                                                                      NTP C#: 04502        
PATHOLOGIST: K. MURTHY                       S. EUSTIS                                                         CAS: 1271-19-8       
------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
               REASONS FOR REMOVAL:    ALL                                                                                          
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
               REMOVAL DATE RANGE:     ALL                                                                                          
                                                                                                                                    
               TREATMENT GROUPS:       INCLUDE ALL                                                                                  
NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08    
LAB: Mason                                                TITANOCENE DICHLORIDE                                DATE: 09/06/94      
EXPERIMENT: 05047 TEST: 01                                                                                     TIME: 22:02:50      
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                       
CONT: N01ES9561904          ROUTE: GAVAGE                                                                      NTP C#: 04502       
PATHOLOGIST: K. MURTHY                       S. EUSTIS                                                         CAS: 1271-19-8      
 
 
 
 
 
                                                    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: Mason                                                TITANOCENE DICHLORIDE                                DATE: 09/06/94       
EXPERIMENT: 05047 TEST: 01                                                                                     TIME: 22:02:50       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                        
CONT: N01ES9561904          ROUTE: GAVAGE                                                                      NTP C#: 04502        
PATHOLOGIST: K. MURTHY                       S. EUSTIS                                                         CAS: 1271-19-8       
 
 
 
 
 
                                     SUMMARY OF STATISTICALLY SIGNIFICANT (P<=.05) RESULTS
                                     IN THE ANALYSIS OF THE STUDY OF TITANOCENE DICHLORIDE
 
              ====================================================================================================
 
                                                           MALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Liver                         Hepatocellular Adenoma
                                                           Hepatocellular Carcinoma or Hepatocellular Adenoma
                                                           Hepatocellular Carcinoma, Hepatocellular Adenoma, or Hepatoblastoma
                             Pancreas                      Adenoma
                             Pituitary Gland: Pars Distalis or Unspecified Site
                                                           Adenoma
                             Stomach, Forestomach          Squamous Cell Carcinoma or Papilloma Squamous
                                                           Squamous Cell Papilloma
                             Testes                        Adenoma
                             All Organs                    Mesothelioma Benign, Malignant, NOS
                                                           Benign Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
 
                                                           FEMALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Clitoral/Preputial Gland      Adenoma
                                                           Carcinoma or Adenoma
                             Mammary Gland                 Carcinoma
                                                           Carcinoma or Adenoma
                             Pituitary Gland: Pars Distalis or Unspecified Site
                                                           Adenoma
                             All Organs                    Benign Tumors
                                                           Malignant Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   1
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma Benign                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    20/60 (33%)     21/60 (35%)     17/59 (29%)     |     6/58 (10%)      7/60 (12%)      6/59 (10%)     |
|ADJUSTED (b)           |     46.3%           65.1%           58.3%          |     16.0%           21.9%           18.2%          |
|TERMINAL (d)           |    18/41 (44%)     19/30 (63%)     12/24 (50%)     |     5/36 (14%)      5/30 (17%)      4/30 (13%)     |
|FIRST INCIDENCE (DAYS) |      670             536             662           |      702             721             674           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.078         P=0.089         P=0.123        |     P=0.414         P=0.368         P=0.475        |
|INCIDENTAL TUMOR       |     P=0.132         P=0.119         P=0.195        |     P=0.436         P=0.439         P=0.503        |
|LOGISTIC REGRESSION    |     P=0.152         P=0.126         P=0.198        |     P=0.416         P=0.393         P=0.487        |
|COCHRAN-ARMITAGE       |     P=0.335N                                       |     P=0.547N                                       |
|FISHER EXACT           |                     P=0.500         P=0.369N       |                     P=0.526         P=0.607N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma Malignant                                                                                                  |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       1/60 (2%)       1/59 (2%)      |     1/58 (2%)       0/60 (0%)       0/59 (0%)      |
|ADJUSTED (b)           |      6.5%            2.3%            2.8%          |      2.8%            0.0%            0.0%          |
|TERMINAL (d)           |     1/41 (2%)       0/30 (0%)       0/24 (0%)      |     1/36 (3%)       0/30 (0%)       0/30 (0%)      |
|FIRST INCIDENCE (DAYS) |      647             603             620           |      743 (T)         ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.332N        P=0.407N        P=0.482N       |     P=0.298N        P=0.536N        P=0.536N       |
|INCIDENTAL TUMOR       |     P=0.211N        P=0.315N        P=0.338N       |     P=0.298N        P=0.536N        P=0.536N       |
|LOGISTIC REGRESSION    |     P=0.222N        P=0.305N        P=0.361N       |     P=0.298N        P=0.536N        P=0.536N       |
|COCHRAN-ARMITAGE       |     P=0.206N                                       |     P=0.266N                                       |
|FISHER EXACT           |                     P=0.309N        P=0.316N       |                     P=0.492N        P=0.496N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   2
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma: Benign, Complex, Malignant, NOS                                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    22/60 (37%)     22/60 (37%)     18/59 (31%)     |     7/58 (12%)      7/60 (12%)      6/59 (10%)     |
|ADJUSTED (b)           |     49.6%           65.9%           59.4%          |     18.7%           21.9%           18.2%          |
|TERMINAL (d)           |    19/41 (46%)     19/30 (63%)     12/24 (50%)     |     6/36 (17%)      5/30 (17%)      4/30 (13%)     |
|FIRST INCIDENCE (DAYS) |      647             536             620           |      702             721             674           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.103         P=0.122         P=0.149        |     P=0.523         P=0.473         P=0.583        |
|INCIDENTAL TUMOR       |     P=0.189         P=0.177         P=0.256        |     P=0.548         P=0.545         P=0.610        |
|LOGISTIC REGRESSION    |     P=0.220         P=0.188         P=0.273        |     P=0.528         P=0.502         P=0.595        |
|COCHRAN-ARMITAGE       |     P=0.272N                                       |     P=0.429N                                       |
|FISHER EXACT           |                     P=0.575N        P=0.303N       |                     P=0.585N        P=0.487N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/56 (7%)       1/59 (2%)       3/56 (5%)      |    12/56 (21%)      8/55 (15%)      2/56 (4%)      |
|ADJUSTED (b)           |     10.8%            2.0%           11.1%          |     31.9%           20.7%            5.2%          |
|TERMINAL (d)           |     4/37 (11%)      0/30 (0%)       2/24 (8%)      |    10/34 (29%)      4/30 (13%)      1/31 (3%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         537             662           |      384             510             485           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.574         P=0.245N        P=0.585        |     P=0.009N**      P=0.323N        P=0.009N**     |
|INCIDENTAL TUMOR       |     P=0.534N        P=0.164N        P=0.614        |     P=0.003N**      P=0.212N        P=0.003N**     |
|LOGISTIC REGRESSION    |     P=0.518N        P=0.191N        P=0.640        |     P=0.005N**      P=0.259N        P=0.007N**     |
|COCHRAN-ARMITAGE       |     P=0.411N                                       |     P=0.004N**                                     |
|FISHER EXACT           |                     P=0.166N        P=0.500N       |                     P=0.244N        P=0.004N**     |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   3
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     5/56 (9%)       1/59 (2%)       4/56 (7%)      |    13/56 (23%)      9/55 (16%)      2/56 (4%)      |
|ADJUSTED (b)           |     12.8%            2.0%           14.0%          |     34.8%           23.8%            5.2%          |
|TERMINAL (d)           |     4/37 (11%)      0/30 (0%)       2/24 (8%)      |    11/34 (32%)      5/30 (17%)      1/31 (3%)      |
|FIRST INCIDENCE (DAYS) |      716             537             662           |      384             510             485           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.516         P=0.163N        P=0.510        |     P=0.006N**      P=0.338N        P=0.005N**     |
|INCIDENTAL TUMOR       |     P=0.531N        P=0.099N        P=0.601        |     P=0.002N**      P=0.228N        P=0.002N**     |
|LOGISTIC REGRESSION    |     P=0.541N        P=0.115N        P=0.597        |     P=0.003N**      P=0.277N        P=0.004N**     |
|COCHRAN-ARMITAGE       |     P=0.420N                                       |     P=0.002N**                                     |
|FISHER EXACT           |                     P=0.092N        P=0.500N       |                     P=0.253N        P=0.002N**     |
|=================================================================================================================================|
|                                                                                                                                 |
|Islets, Pancreatic                                                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     5/58 (9%)       5/56 (9%)       1/59 (2%)      |     2/59 (3%)       1/61 (2%)       0/59 (0%)      |
|ADJUSTED (b)           |     10.8%           16.7%            4.3%          |      5.6%            3.3%            0.0%          |
|TERMINAL (d)           |     2/39 (5%)       5/30 (17%)      1/23 (4%)      |     2/36 (6%)       1/30 (3%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      577             738 (T)         738 (T)       |      743 (T)         743 (T)         ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.257N        P=0.459         P=0.246N       |     P=0.172N        P=0.564N        P=0.272N       |
|INCIDENTAL TUMOR       |     P=0.199N        P=0.501         P=0.158N       |     P=0.172N        P=0.564N        P=0.272N       |
|LOGISTIC REGRESSION    |     P=0.186N        P=0.519         P=0.156N       |     P=0.172N        P=0.564N        P=0.272N       |
|COCHRAN-ARMITAGE       |     P=0.088N                                       |     P=0.141N                                       |
|FISHER EXACT           |                     P=0.606         P=0.099N       |                     P=0.487N        P=0.248N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   4
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Adenoma                                                                                                      |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       3/59 (5%)       7/60 (12%)     |     0/60 (0%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      9.8%           10.0%           26.3%          |      0.0%            3.3%            6.5%          |
|TERMINAL (d)           |     4/41 (10%)      3/30 (10%)      5/24 (21%)     |     0/37 (0%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         738 (T)         708           |      ---             743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.042 *       P=0.643         P=0.057        |     P=0.119         P=0.458         P=0.200        |
|INCIDENTAL TUMOR       |     P=0.053         P=0.643         P=0.076        |     P=0.119         P=0.458         P=0.200        |
|LOGISTIC REGRESSION    |     P=0.052         P=0.643         P=0.072        |     P=0.119         P=0.458         P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.198                                        |     P=0.142                                        |
|FISHER EXACT           |                     P=0.509N        P=0.264        |                     P=0.504         P=0.248        |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Carcinoma or Hepatocellular Adenoma                                                                          |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       3/59 (5%)       8/60 (13%)     |     0/60 (0%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      9.8%           10.0%           28.1%          |      0.0%            3.3%            6.5%          |
|TERMINAL (d)           |     4/41 (10%)      3/30 (10%)      5/24 (21%)     |     0/37 (0%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         738 (T)         612           |      ---             743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.022 *       P=0.643         P=0.032 *      |     P=0.119         P=0.458         P=0.200        |
|INCIDENTAL TUMOR       |     P=0.031 *       P=0.643         P=0.051        |     P=0.119         P=0.458         P=0.200        |
|LOGISTIC REGRESSION    |     P=0.032 *       P=0.643         P=0.050 *      |     P=0.119         P=0.458         P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.124                                        |     P=0.142                                        |
|FISHER EXACT           |                     P=0.509N        P=0.181        |                     P=0.504         P=0.248        |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   5
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Carcinoma, Hepatocellular Adenoma, or Hepatoblastoma                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       3/59 (5%)       8/60 (13%)     |     0/60 (0%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      9.8%           10.0%           28.1%          |      0.0%            3.3%            6.5%          |
|TERMINAL (d)           |     4/41 (10%)      3/30 (10%)      5/24 (21%)     |     0/37 (0%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         738 (T)         612           |      ---             743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.022 *       P=0.643         P=0.032 *      |     P=0.119         P=0.458         P=0.200        |
|INCIDENTAL TUMOR       |     P=0.031 *       P=0.643         P=0.051        |     P=0.119         P=0.458         P=0.200        |
|LOGISTIC REGRESSION    |     P=0.032 *       P=0.643         P=0.050 *      |     P=0.119         P=0.458         P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.124                                        |     P=0.142                                        |
|FISHER EXACT           |                     P=0.509N        P=0.181        |                     P=0.504         P=0.248        |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Adenoma                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       2/60 (3%)       5/60 (8%)      |     1/60 (2%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      6.6%            6.7%           20.8%          |      2.7%            3.3%            6.5%          |
|TERMINAL (d)           |     1/41 (2%)       2/30 (7%)       5/24 (21%)     |     1/37 (3%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      681             738 (T)         738 (T)       |      743 (T)         743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.098         P=0.633N        P=0.132        |     P=0.324         P=0.715         P=0.438        |
|INCIDENTAL TUMOR       |     P=0.119         P=0.603N        P=0.167        |     P=0.324         P=0.715         P=0.438        |
|LOGISTIC REGRESSION    |     P=0.122         P=0.592N        P=0.169        |     P=0.324         P=0.715         P=0.438        |
|COCHRAN-ARMITAGE       |     P=0.275                                        |     P=0.378                                        |
|FISHER EXACT           |                     P=0.500N        P=0.359        |                     P=0.748N        P=0.500        |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   6
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Carcinoma or Alveolar/Bronchiolar Adenoma                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       2/60 (3%)       5/60 (8%)      |     2/60 (3%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      8.4%            6.7%           20.8%          |      5.4%            3.3%            6.5%          |
|TERMINAL (d)           |     1/41 (2%)       2/30 (7%)       5/24 (21%)     |     2/37 (5%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      605             738 (T)         738 (T)       |      743 (T)         743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.190         P=0.475N        P=0.230        |     P=0.542         P=0.573N        P=0.630        |
|INCIDENTAL TUMOR       |     P=0.239         P=0.396N        P=0.307        |     P=0.542         P=0.573N        P=0.630        |
|LOGISTIC REGRESSION    |     P=0.246         P=0.390N        P=0.310        |     P=0.542         P=0.573N        P=0.630        |
|COCHRAN-ARMITAGE       |     P=0.424                                        |     P=0.610                                        |
|FISHER EXACT           |                     P=0.340N        P=0.500        |                     P=0.494N        P=0.691N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |     3/60 (5%)       1/61 (2%)       0/60 (0%)      |
|ADJUSTED (b)           |      0.0%            0.0%            0.0%          |      7.0%            1.7%            0.0%          |
|TERMINAL (d)           |     0/41 (0%)       0/30 (0%)       0/24 (0%)      |     2/37 (5%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      ---             ---             ---           |      342             350             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |       (e)             (e)             (e)          |     P=0.077N        P=0.341N        P=0.149N       |
|INCIDENTAL TUMOR       |       (e)             (e)             (e)          |     P=0.018N*       P=0.331N        P=0.072N       |
|LOGISTIC REGRESSION    |       (e)             (e)             (e)          |     P=0.023N*       P=0.227N        P=0.084N       |
|COCHRAN-ARMITAGE       |       (e)                                          |     P=0.060N                                       |
|FISHER EXACT           |                       (e)             (e)          |                     P=0.303N        P=0.122N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   7
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |     4/60 (7%)       2/61 (3%)       0/60 (0%)      |
|ADJUSTED (b)           |      0.0%            0.0%            0.0%          |      9.7%            3.6%            0.0%          |
|TERMINAL (d)           |     0/41 (0%)       0/30 (0%)       0/24 (0%)      |     3/37 (8%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      ---             ---             ---           |      342             350             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |       (e)             (e)             (e)          |     P=0.055N        P=0.389N        P=0.085N       |
|INCIDENTAL TUMOR       |       (e)             (e)             (e)          |     P=0.017N*       P=0.355N        P=0.041N*      |
|LOGISTIC REGRESSION    |       (e)             (e)             (e)          |     P=0.015N*       P=0.261N        P=0.051N       |
|COCHRAN-ARMITAGE       |       (e)                                          |     P=0.037N*                                      |
|FISHER EXACT           |                       (e)             (e)          |                     P=0.332N        P=0.059N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroadenoma                                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       6/60 (10%)      2/60 (3%)      |    26/60 (43%)     24/61 (39%)     18/60 (30%)     |
|ADJUSTED (b)           |      9.8%           19.2%            8.3%          |     61.3%           56.8%           50.5%          |
|TERMINAL (d)           |     4/41 (10%)      5/30 (17%)      2/24 (8%)      |    21/37 (57%)     13/30 (43%)     14/31 (45%)     |
|FIRST INCIDENCE (DAYS) |      738 (T)         717             738 (T)       |      639             504             496           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.553         P=0.196         P=0.599N       |     P=0.283N        P=0.387         P=0.285N       |
|INCIDENTAL TUMOR       |     P=0.570N        P=0.204         P=0.599N       |     P=0.224N        P=0.544N        P=0.250N       |
|LOGISTIC REGRESSION    |     P=0.567N        P=0.200         P=0.599N       |     P=0.238N        P=0.571N        P=0.280N       |
|COCHRAN-ARMITAGE       |     P=0.292N                                       |     P=0.079N                                       |
|FISHER EXACT           |                     P=0.372         P=0.340N       |                     P=0.397N        P=0.092N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   8
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma or Adenoma                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       6/60 (10%)      2/60 (3%)      |    26/60 (43%)     25/61 (41%)     18/60 (30%)     |
|ADJUSTED (b)           |      9.8%           19.2%            8.3%          |     61.3%           57.6%           50.5%          |
|TERMINAL (d)           |     4/41 (10%)      5/30 (17%)      2/24 (8%)      |    21/37 (57%)     13/30 (43%)     14/31 (45%)     |
|FIRST INCIDENCE (DAYS) |      738 (T)         717             738 (T)       |      639             504             496           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.553         P=0.196         P=0.599N       |     P=0.289N        P=0.323         P=0.285N       |
|INCIDENTAL TUMOR       |     P=0.570N        P=0.204         P=0.599N       |     P=0.236N        P=0.544         P=0.250N       |
|LOGISTIC REGRESSION    |     P=0.567N        P=0.200         P=0.599N       |     P=0.234N        P=0.523         P=0.280N       |
|COCHRAN-ARMITAGE       |     P=0.292N                                       |     P=0.079N                                       |
|FISHER EXACT           |                     P=0.372         P=0.340N       |                     P=0.469N        P=0.092N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma, Carcinoma, or Adenoma                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     4/60 (7%)       6/60 (10%)      2/60 (3%)      |    27/60 (45%)     26/61 (43%)     18/60 (30%)     |
|ADJUSTED (b)           |      9.8%           19.2%            8.3%          |     62.0%           58.3%           50.5%          |
|TERMINAL (d)           |     4/41 (10%)      5/30 (17%)      2/24 (8%)      |    21/37 (57%)     13/30 (43%)     14/31 (45%)     |
|FIRST INCIDENCE (DAYS) |      738 (T)         717             738 (T)       |      342             350             496           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.553         P=0.196         P=0.599N       |     P=0.239N        P=0.329         P=0.228N       |
|INCIDENTAL TUMOR       |     P=0.570N        P=0.204         P=0.599N       |     P=0.141N        P=0.543         P=0.164N       |
|LOGISTIC REGRESSION    |     P=0.567N        P=0.200         P=0.599N       |     P=0.151N        P=0.552N        P=0.198N       |
|COCHRAN-ARMITAGE       |     P=0.292N                                       |     P=0.056N                                       |
|FISHER EXACT           |                     P=0.372         P=0.340N       |                     P=0.468N        P=0.066N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE   9
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Pancreas                                                                                                                         |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/59 (0%)       4/56 (7%)       0/59 (0%)      |     1/60 (2%)       1/61 (2%)       1/59 (2%)      |
|ADJUSTED (b)           |      0.0%           12.1%            0.0%          |      2.7%            3.3%            3.2%          |
|TERMINAL (d)           |     0/40 (0%)       3/30 (10%)      0/23 (0%)      |     1/37 (3%)       1/30 (3%)       1/31 (3%)      |
|FIRST INCIDENCE (DAYS) |      ---             611             ---           |      743 (T)         743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.468         P=0.036 *         (e)          |     P=0.588         P=0.715         P=0.722        |
|INCIDENTAL TUMOR       |     P=0.511         P=0.047 *         (e)          |     P=0.588         P=0.715         P=0.722        |
|LOGISTIC REGRESSION    |     P=0.525         P=0.043 *         (e)          |     P=0.588         P=0.715         P=0.722        |
|COCHRAN-ARMITAGE       |     P=0.621                                        |     P=0.635                                        |
|FISHER EXACT           |                     P=0.053           (e)          |                     P=0.748N        P=0.748        |
|=================================================================================================================================|
|                                                                                                                                 |
|Pituitary Gland: Pars Distalis or Unspecified Site                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    23/56 (41%)     20/59 (34%)     14/56 (25%)     |    29/59 (49%)     23/59 (39%)     16/60 (27%)     |
|ADJUSTED (b)           |     50.1%           52.2%           39.7%          |     62.3%           58.0%           42.3%          |
|TERMINAL (d)           |    17/39 (44%)     13/30 (43%)      6/24 (25%)     |    20/37 (54%)     15/30 (50%)     10/31 (32%)     |
|FIRST INCIDENCE (DAYS) |      579             400             465           |      549             574             575           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.481N        P=0.402         P=0.493N       |     P=0.079N        P=0.481N        P=0.089N       |
|INCIDENTAL TUMOR       |     P=0.189N        P=0.517N        P=0.194N       |     P=0.072N        P=0.276N        P=0.083N       |
|LOGISTIC REGRESSION    |     P=0.159N        P=0.478N        P=0.171N       |     P=0.032N*       P=0.267N        P=0.041N*      |
|COCHRAN-ARMITAGE       |     P=0.044N*                                      |     P=0.008N**                                     |
|FISHER EXACT           |                     P=0.274N        P=0.054N       |                     P=0.177N        P=0.009N**     |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  10
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Keratoacanthoma                                                                                                             |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       0/60 (0%)       1/60 (2%)      |     0/60 (0%)       0/61 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      4.9%            0.0%            4.2%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     2/41 (5%)       0/30 (0%)       1/24 (4%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         ---             738 (T)       |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.511N        P=0.309N        P=0.683N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.511N        P=0.309N        P=0.683N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.511N        P=0.309N        P=0.683N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.361N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.248N        P=0.500N       |                       (e)             (e)          |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Trichoepithelioma, Kertatocanthoma, Squamous Cell Carcinoma,                                                                |
|     Basal Cell Carcinoma or Adenoma, Papilloma Squamous, or Papilloma                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       0/60 (0%)       1/60 (2%)      |     1/60 (2%)       0/61 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      7.3%            0.0%            4.2%          |      2.7%            0.0%            0.0%          |
|TERMINAL (d)           |     3/41 (7%)       0/30 (0%)       1/24 (4%)      |     1/37 (3%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         ---             738 (T)       |      743 (T)         ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.311N        P=0.181N        P=0.510N       |     P=0.299N        P=0.542N        P=0.535N       |
|INCIDENTAL TUMOR       |     P=0.311N        P=0.181N        P=0.510N       |     P=0.299N        P=0.542N        P=0.535N       |
|LOGISTIC REGRESSION    |     P=0.311N        P=0.181N        P=0.510N       |     P=0.299N        P=0.542N        P=0.535N       |
|COCHRAN-ARMITAGE       |     P=0.176N                                       |     P=0.269N                                       |
|FISHER EXACT           |                     P=0.122N        P=0.309N       |                     P=0.496N        P=0.500N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  11
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Fibroma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     5/60 (8%)       2/60 (3%)       3/60 (5%)      |     0/60 (0%)       1/61 (2%)       0/60 (0%)      |
|ADJUSTED (b)           |     11.0%            5.3%            9.1%          |      0.0%            2.9%            0.0%          |
|TERMINAL (d)           |     3/41 (7%)       1/30 (3%)       1/24 (4%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      499             553             465           |      ---             707             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.494N        P=0.339N        P=0.607N       |     P=0.698         P=0.468           (e)          |
|INCIDENTAL TUMOR       |     P=0.313N        P=0.212N        P=0.371N       |     P=0.714         P=0.533           (e)          |
|LOGISTIC REGRESSION    |     P=0.298N        P=0.215N        P=0.392N       |     P=0.712         P=0.489           (e)          |
|COCHRAN-ARMITAGE       |     P=0.275N                                       |     P=0.731                                        |
|FISHER EXACT           |                     P=0.219N        P=0.359N       |                     P=0.504           (e)          |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Fibrosarcoma                                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       2/60 (3%)       0/60 (0%)      |     1/60 (2%)       0/61 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      2.4%            5.0%            0.0%          |      2.2%            0.0%            0.0%          |
|TERMINAL (d)           |     1/41 (2%)       1/30 (3%)       0/24 (0%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         306             ---           |      688             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.473N        P=0.424         P=0.607N       |     P=0.313N        P=0.538N        P=0.560N       |
|INCIDENTAL TUMOR       |     P=0.226N        P=0.691         P=0.607N       |     P=0.286N        P=0.467N        P=0.540N       |
|LOGISTIC REGRESSION    |     P=0.278N        P=0.627         P=0.607N       |     P=0.278N        P=0.501N        P=0.517N       |
|COCHRAN-ARMITAGE       |     P=0.361N                                       |     P=0.269N                                       |
|FISHER EXACT           |                     P=0.500         P=0.500N       |                     P=0.496N        P=0.500N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  12
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Neurofibrosarcoma, Fibrosarcoma, Sarcoma,                                                                                   |
|     Neurofibroma, or Fibroma                                                                                                    |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     7/60 (12%)      4/60 (7%)       3/60 (5%)      |     1/60 (2%)       1/61 (2%)       1/60 (2%)      |
|ADJUSTED (b)           |     15.7%           10.2%            9.1%          |      2.2%            2.9%            1.9%          |
|TERMINAL (d)           |     5/41 (12%)      2/30 (7%)       1/24 (4%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      499             306             465           |      688             707             457           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.312N        P=0.426N        P=0.403N       |     P=0.584         P=0.721         P=0.718        |
|INCIDENTAL TUMOR       |     P=0.111N        P=0.196N        P=0.211N       |     P=0.557N        P=0.727N        P=0.644N       |
|LOGISTIC REGRESSION    |     P=0.113N        P=0.220N        P=0.215N       |     P=0.597N        P=0.758         P=0.705N       |
|COCHRAN-ARMITAGE       |     P=0.116N                                       |     P=0.640                                        |
|FISHER EXACT           |                     P=0.264N        P=0.161N       |                     P=0.748N        P=0.752N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Neurofibrosarcoma, Fibrosarcoma, or Sarcoma                                                                                 |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       2/60 (3%)       0/60 (0%)      |     1/60 (2%)       1/61 (2%)       1/60 (2%)      |
|ADJUSTED (b)           |      4.9%            5.0%            0.0%          |      2.2%            2.9%            1.9%          |
|TERMINAL (d)           |     2/41 (5%)       1/30 (3%)       0/24 (0%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         306             ---           |      688             707             457           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.284N        P=0.604         P=0.362N       |     P=0.584         P=0.721         P=0.718        |
|INCIDENTAL TUMOR       |     P=0.116N        P=0.609N        P=0.362N       |     P=0.557N        P=0.727N        P=0.644N       |
|LOGISTIC REGRESSION    |     P=0.145N        P=0.634N        P=0.362N       |     P=0.597N        P=0.758         P=0.705N       |
|COCHRAN-ARMITAGE       |     P=0.176N                                       |     P=0.640                                        |
|FISHER EXACT           |                     P=0.691N        P=0.248N       |                     P=0.748N        P=0.752N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  13
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Stomach, Forestomach                                                                                                             |
|     Squamous Cell Carcinoma or Papilloma Squamous                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       4/60 (7%)       1/60 (2%)      |     0/60 (0%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      0.0%           13.3%            4.2%          |      0.0%            3.3%            6.5%          |
|TERMINAL (d)           |     0/41 (0%)       4/30 (13%)      1/24 (4%)      |     0/37 (0%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      ---             738 (T)         738 (T)       |      ---             743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|INCIDENTAL TUMOR       |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|LOGISTIC REGRESSION    |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.391                                        |     P=0.142                                        |
|FISHER EXACT           |                     P=0.059         P=0.500        |                     P=0.504         P=0.248        |
|=================================================================================================================================|
|                                                                                                                                 |
|Stomach, Forestomach                                                                                                             |
|     Squamous Cell Papilloma                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       4/60 (7%)       1/60 (2%)      |     0/60 (0%)       1/61 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |      0.0%           13.3%            4.2%          |      0.0%            3.3%            6.5%          |
|TERMINAL (d)           |     0/41 (0%)       4/30 (13%)      1/24 (4%)      |     0/37 (0%)       1/30 (3%)       2/31 (6%)      |
|FIRST INCIDENCE (DAYS) |      ---             738 (T)         738 (T)       |      ---             743 (T)         743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|INCIDENTAL TUMOR       |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|LOGISTIC REGRESSION    |     P=0.215         P=0.031 *       P=0.393        |     P=0.119         P=0.458         P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.391                                        |     P=0.142                                        |
|FISHER EXACT           |                     P=0.059         P=0.500        |                     P=0.504         P=0.248        |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  14
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Testes                                                                                                                           |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    51/60 (85%)     50/60 (83%)     46/60 (77%)     |                                                    |
|ADJUSTED (b)           |     92.6%           96.1%          100.0%          |                                                    |
|TERMINAL (d)           |    37/41 (90%)     28/30 (93%)     24/24 (100%)    |                                                    |
|FIRST INCIDENCE (DAYS) |      474             474             405           |                                                    |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.004 **      P=0.031 *       P=0.004 **     |                                                    |
|INCIDENTAL TUMOR       |     P=0.037 *       P=0.263         P=0.057        |                                                    |
|LOGISTIC REGRESSION    |     P=0.018 *       P=0.195         P=0.042 *      |                                                    |
|COCHRAN-ARMITAGE       |     P=0.144N                                       |                                                    |
|FISHER EXACT           |                     P=0.500N        P=0.177N       |                                                    |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    12/60 (20%)      9/55 (16%)      9/58 (16%)     |     9/60 (15%)      8/57 (14%)      7/59 (12%)     |
|ADJUSTED (b)           |     29.3%           23.7%           26.8%          |     22.4%           22.4%           21.4%          |
|TERMINAL (d)           |    12/41 (29%)      4/30 (13%)      2/24 (8%)      |     7/37 (19%)      4/30 (13%)      6/31 (19%)     |
|FIRST INCIDENCE (DAYS) |      738 (T)         509             612           |      622             631             653           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.383         P=0.594         P=0.405        |     P=0.500N        P=0.546         P=0.548N       |
|INCIDENTAL TUMOR       |     P=0.544N        P=0.526N        P=0.534        |     P=0.524N        P=0.573N        P=0.574N       |
|LOGISTIC REGRESSION    |     P=0.549         P=0.512N        P=0.538        |     P=0.501N        P=0.601N        P=0.558N       |
|COCHRAN-ARMITAGE       |     P=0.300N                                       |     P=0.358N                                       |
|FISHER EXACT           |                     P=0.398N        P=0.347N       |                     P=0.546N        P=0.409N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  15
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       0/55 (0%)       1/58 (2%)      |     1/60 (2%)       3/57 (5%)       0/59 (0%)      |
|ADJUSTED (b)           |      2.4%            0.0%            3.2%          |      1.8%           10.0%            0.0%          |
|TERMINAL (d)           |     1/41 (2%)       0/30 (0%)       0/24 (0%)      |     0/37 (0%)       3/30 (10%)      0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      738 (T)         ---             690           |      598             743 (T)         ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.565         P=0.562N        P=0.654        |     P=0.443N        P=0.243         P=0.549N       |
|INCIDENTAL TUMOR       |     P=0.608         P=0.562N        P=0.702        |     P=0.469N        P=0.262         P=0.638N       |
|LOGISTIC REGRESSION    |     P=0.591         P=0.562N        P=0.685        |     P=0.424N        P=0.277         P=0.461N       |
|COCHRAN-ARMITAGE       |     P=0.659                                        |     P=0.385N                                       |
|FISHER EXACT           |                     P=0.522N        P=0.744        |                     P=0.290         P=0.504N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    13/60 (22%)      9/55 (16%)      9/58 (16%)     |    10/60 (17%)     11/57 (19%)      7/59 (12%)     |
|ADJUSTED (b)           |     31.7%           23.7%           26.8%          |     23.8%           31.4%           21.4%          |
|TERMINAL (d)           |    13/41 (32%)      4/30 (13%)      2/24 (8%)      |     7/37 (19%)      7/30 (23%)      6/31 (19%)     |
|FIRST INCIDENCE (DAYS) |      738 (T)         509             612           |      598             631             653           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.460         P=0.516N        P=0.476        |     P=0.428N        P=0.326         P=0.455N       |
|INCIDENTAL TUMOR       |     P=0.463N        P=0.445N        P=0.589N       |     P=0.459N        P=0.409         P=0.501N       |
|LOGISTIC REGRESSION    |     P=0.467N        P=0.430N        P=0.583N       |     P=0.420N        P=0.394         P=0.446N       |
|COCHRAN-ARMITAGE       |     P=0.225N                                       |     P=0.279N                                       |
|FISHER EXACT           |                     P=0.315N        P=0.268N       |                     P=0.448         P=0.314N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  16
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: Follicular Cell                                                                                                   |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       1/55 (2%)       1/58 (2%)      |     1/60 (2%)       0/57 (0%)       1/59 (2%)      |
|ADJUSTED (b)           |      4.4%            3.3%            4.2%          |      2.7%            0.0%            2.9%          |
|TERMINAL (d)           |     1/41 (2%)       1/30 (3%)       1/24 (4%)      |     1/37 (3%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      647             738 (T)         738 (T)       |      743 (T)         ---             693           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.543N        P=0.603N        P=0.667N       |     P=0.615         P=0.542N        P=0.709        |
|INCIDENTAL TUMOR       |     P=0.509N        P=0.597N        P=0.622N       |     P=0.630         P=0.542N        P=0.718        |
|LOGISTIC REGRESSION    |     P=0.495N        P=0.566N        P=0.611N       |     P=0.631         P=0.542N        P=0.725        |
|COCHRAN-ARMITAGE       |     P=0.391N                                       |     P=0.664                                        |
|FISHER EXACT           |                     P=0.533N        P=0.513N       |                     P=0.513N        P=0.748        |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Polyp Stromal                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    |    11/60 (18%)     10/61 (16%)     16/60 (27%)     |
|ADJUSTED (b)           |                                                    |     25.3%           25.8%           43.2%          |
|TERMINAL (d)           |                                                    |     7/37 (19%)      5/30 (17%)     11/31 (35%)     |
|FIRST INCIDENCE (DAYS) |                                                    |      384             570             493           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |     P=0.072         P=0.525         P=0.087        |
|INCIDENTAL TUMOR       |                                                    |     P=0.067         P=0.487N        P=0.100        |
|LOGISTIC REGRESSION    |                                                    |     P=0.086         P=0.504N        P=0.103        |
|COCHRAN-ARMITAGE       |                                                    |     P=0.154                                        |
|FISHER EXACT           |                                                    |                     P=0.483N        P=0.191        |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  17
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|Zymbal's Gland                                                                                                                   |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       2/60 (3%)       1/60 (2%)      |     0/60 (0%)       0/61 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      6.7%            5.2%            4.2%          |      0.0%            0.0%            3.2%          |
|TERMINAL (d)           |     2/41 (5%)       1/30 (3%)       1/24 (4%)      |     0/37 (0%)       0/30 (0%)       1/31 (3%)      |
|FIRST INCIDENCE (DAYS) |      605             484             738 (T)       |      ---             ---             743 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.379N        P=0.612N        P=0.482N       |     P=0.250           (e)           P=0.465        |
|INCIDENTAL TUMOR       |     P=0.278N        P=0.456N        P=0.426N       |     P=0.250           (e)           P=0.465        |
|LOGISTIC REGRESSION    |     P=0.258N        P=0.474N        P=0.406N       |     P=0.250           (e)           P=0.465        |
|COCHRAN-ARMITAGE       |     P=0.223N                                       |     P=0.269                                        |
|FISHER EXACT           |                     P=0.500N        P=0.309N       |                       (e)           P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Leukemia: Lymphocytic, Monocytic, Mononuclear,                                                                              |
|     or Undifferentiated                                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    15/60 (25%)     12/60 (20%)     11/60 (18%)     |    21/60 (35%)     20/61 (33%)     15/60 (25%)     |
|ADJUSTED (b)           |     30.9%           36.3%           35.3%          |     43.3%           45.5%           41.7%          |
|TERMINAL (d)           |     9/41 (22%)     10/30 (33%)      5/24 (21%)     |    11/37 (30%)      7/30 (23%)     11/31 (35%)     |
|FIRST INCIDENCE (DAYS) |      474             474             612           |      598             570             344           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.356         P=0.514         P=0.407        |     P=0.372N        P=0.403         P=0.377N       |
|INCIDENTAL TUMOR       |     P=0.511N        P=0.501N        P=0.493N       |     P=0.370N        P=0.443N        P=0.406N       |
|LOGISTIC REGRESSION    |     P=0.512N        P=0.481N        P=0.537N       |     P=0.252N        P=0.477N        P=0.283N       |
|COCHRAN-ARMITAGE       |     P=0.217N                                       |     P=0.139N                                       |
|FISHER EXACT           |                     P=0.331N        P=0.253N       |                     P=0.474N        P=0.160N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  18
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Mesothelioma Benign, Malignant, NOS                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       3/60 (5%)       4/60 (7%)      |     0/60 (0%)       0/61 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      0.0%            8.7%           13.6%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     0/41 (0%)       2/30 (7%)       2/24 (8%)      |     0/37 (0%)       0/30 (0%)       0/31 (0%)      |
|FIRST INCIDENCE (DAYS) |      ---             583             618           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.017 *       P=0.081         P=0.023 *      |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.026 *       P=0.107         P=0.042 *      |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.027 *       P=0.105         P=0.035 *      |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.049 *                                      |       (e)                                          |
|FISHER EXACT           |                     P=0.122         P=0.059        |                       (e)             (e)          |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Benign Tumors                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    59/60 (98%)     55/60 (92%)     48/60 (80%)     |    46/60 (77%)     50/61 (82%)     40/60 (67%)     |
|ADJUSTED (b)           |    100.0%          100.0%          100.0%          |     88.2%           94.3%           88.7%          |
|TERMINAL (d)           |    41/41 (100%)    30/30 (100%)    24/24 (100%)    |    31/37 (84%)     27/30 (90%)     26/31 (84%)     |
|FIRST INCIDENCE (DAYS) |      474             400             405           |      384             504             485           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.021 *       P=0.052         P=0.025 *      |     P=0.366         P=0.046 *       P=0.431        |
|INCIDENTAL TUMOR       |     P=0.609         P=0.700         P=0.729        |     P=0.403         P=0.176         P=0.469        |
|LOGISTIC REGRESSION    |     P=0.396         P=0.556         P=0.572        |     P=0.525         P=0.152         P=0.588        |
|COCHRAN-ARMITAGE       |     P<0.001N**                                     |     P=0.123N                                       |
|FISHER EXACT           |                     P=0.103N        P=0.001N**     |                     P=0.310         P=0.156N       |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  19
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      VEHICLE         0.025 G/        0.05 G/K      |      VEHICLE         0.025 G/        0.05 G/K      |
|                       |      79VM            KG 79 LM        G 79 HM       |      79 VF           KG 79 LF        G 79 HF       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant Tumors                                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    24/60 (40%)     19/60 (32%)     19/60 (32%)     |    30/60 (50%)     25/61 (41%)     18/60 (30%)     |
|ADJUSTED (b)           |     45.4%           50.1%           54.5%          |     59.1%           55.7%           45.6%          |
|TERMINAL (d)           |    13/41 (32%)     13/30 (43%)      9/24 (38%)     |    17/37 (46%)     11/30 (37%)     11/31 (35%)     |
|FIRST INCIDENCE (DAYS) |      474             306             612           |      342             350             344           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.239         P=0.513         P=0.258        |     P=0.136N        P=0.540N        P=0.136N       |
|INCIDENTAL TUMOR       |     P=0.457N        P=0.277N        P=0.525N       |     P=0.060N        P=0.235N        P=0.081N       |
|LOGISTIC REGRESSION    |     P=0.474N        P=0.270N        P=0.532N       |     P=0.037N*       P=0.247N        P=0.044N*      |
|COCHRAN-ARMITAGE       |     P=0.194N                                       |     P=0.016N*                                      |
|FISHER EXACT           |                     P=0.223N        P=0.223N       |                     P=0.208N        P=0.020N*      |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant and Benign Tumors                                                                                                 |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    60/60 (100%)    56/60 (93%)     48/60 (80%)     |    56/60 (93%)     53/61 (87%)     46/60 (77%)     |
|ADJUSTED (b)           |    100.0%          100.0%          100.0%          |     96.5%           96.3%           93.8%          |
|TERMINAL (d)           |    41/41 (100%)    30/30 (100%)    24/24 (100%)    |    35/37 (95%)     28/30 (93%)     28/31 (90%)     |
|FIRST INCIDENCE (DAYS) |      474             306             405           |      342             350             344           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.031 *       P=0.054         P=0.035 *      |     P=0.519N        P=0.226         P=0.524N       |
|INCIDENTAL TUMOR       |     P=0.173N        P=0.500N        P=0.470N       |     P=0.196N        P=0.310N        P=0.265N       |
|LOGISTIC REGRESSION    |     P=0.348N        P=0.853N        P=0.470N       |     P=0.092N        P=0.267N        P=0.119N       |
|COCHRAN-ARMITAGE       |     P<0.001N**                                     |     P=0.007N**                                     |
|FISHER EXACT           |                     P=0.059N        P<0.001N**     |                     P=0.189N        P=0.010N**     |
|=================================================================================================================================|
 
         DATE: 09/06/94                     EXPERIMENT: 05047 TEST: 01                                                 PAGE  20
                          STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- TITANOCENE DICHLORIDE
 
                                                 MALE TERMINAL SACRIFICE AT 106 WEEKS
                                                 FEMALE TERMINAL SACRIFICE AT 107 WEEKS
 
 
 (a)  Number of tumor-bearing animals / number of animals examined at site.
 (b)  Kaplan-Meier estimated lifetime tumor incidence after adjustment for 
      intercurrent mortality.
 (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).

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