National Toxicology Program

National Toxicology Program
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TR 373 Rat Pathology Tables

NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08     
LAB: Microbiological Assoc.                                SUCCINIC ANHYDRIDE                                  DATE: 09/05/94       
EXPERIMENT: 05041 TEST: 01                                                                                     TIME: 13:27:41       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                   PAGE:       1        
CONT: N01ES2802601          ROUTE: GAVAGE                                                                      NTP C#: 55696B       
PATHOLOGIST: W. HALL                                                                                           CAS: 108-30-5        
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               REASONS FOR REMOVAL:    ALL                                                                                          
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
                                                                                                                                    
               REMOVAL DATE RANGE:     ALL                                                                                          
                                                                                                                                    
               TREATMENT GROUPS:       INCLUDE ALL                                                                                  
NTP                                        STATISTICAL ANALYSIS OF PRIMARY TUMORS                              REPORT: PEIRPT08    
LAB: Microbiological Assoc.                                SUCCINIC ANHYDRIDE                                  DATE: 09/05/94      
EXPERIMENT: 05041 TEST: 01                                                                                     TIME: 13:27:41      
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                       
CONT: N01ES2802601          ROUTE: GAVAGE                                                                      NTP C#: 55696B      
PATHOLOGIST: W. HALL                                                                                           CAS: 108-30-5       
 
 
 
 
 
                                                    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
                                                    Larynx
                                                    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: Microbiological Assoc.                                SUCCINIC ANHYDRIDE                                  DATE: 09/05/94       
EXPERIMENT: 05041 TEST: 01                                                                                     TIME: 13:27:41       
TEST TYPE:  CHRONIC                             CAGES FROM 0000 TO LAST CAGE                                                        
CONT: N01ES2802601          ROUTE: GAVAGE                                                                      NTP C#: 55696B       
PATHOLOGIST: W. HALL                                                                                           CAS: 108-30-5        
 
 
 
 
 
                                     SUMMARY OF STATISTICALLY SIGNIFICANT (P<=.05) RESULTS
                                       IN THE ANALYSIS OF THE STUDY OF SUCCINIC ANHYDRIDE
 
              ====================================================================================================
 
                                                           MALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Adrenal Medulla               Pheochromocytoma: Benign, Complex, Malignant, NOS
                             Clitoral/Preputial Gland      Adenoma
                                                           Carcinoma or Adenoma
                             Skin                          Keratoacanthoma
                                                           Trichoepithelioma, Kertatocanthoma, Squamous Cell Carcinoma,
                                                            Basal Cell Carcinoma or Adenoma, Papilloma Squamous, or Papilloma
                             Testes                        Adenoma
                             All Organs                    Benign Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
 
                                                           FEMALE RATS
                                                          -------------
                                 ORGAN                               MORPHOLOGY
                                -------                             ------------
 
                             Mammary Gland                 Fibroadenoma
                                                           Fibroma, Fibroadenoma or Adenoma
                                                           Fibroma, Fibroadenoma, Carcinoma, or Adenoma
                             Pituitary Gland: Pars Distalis or Unspecified Site
                                                           Adenoma
                                                           Carcinoma or Adenoma
                             All Organs                    Benign Tumors
                                                           Malignant and Benign Tumors
 
              ====================================================================================================
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   1
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma Benign                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    17/58 (29%)      9/58 (16%)     12/58 (21%)     |     3/59 (5%)       1/43 (2%)       3/54 (6%)      |
|ADJUSTED (b)           |     38.3%           23.2%           31.9%          |      9.4%            8.3%           11.5%          |
|TERMINAL (d)           |    10/36 (28%)      3/31 (10%)      7/32 (22%)     |     2/31 (6%)       1/12 (8%)       3/26 (12%)     |
|FIRST INCIDENCE (DAYS) |      590             641             625           |      726             729 (T)         729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.266N        P=0.129N        P=0.321N       |     P=0.505         P=0.589N        P=0.586        |
|INCIDENTAL TUMOR       |     P=0.318N        P=0.092N        P=0.390N       |     P=0.499         P=0.593N        P=0.577        |
|LOGISTIC REGRESSION    |     P=0.272N        P=0.096N        P=0.334N       |     P=0.504         P=0.654N        P=0.584        |
|COCHRAN-ARMITAGE       |     P=0.156N                                       |     P=0.550                                        |
|FISHER EXACT           |                     P=0.059N        P=0.196N       |                     P=0.436N        P=0.617        |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma Malignant                                                                                                  |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     5/58 (9%)       5/58 (9%)       2/58 (3%)      |     1/59 (2%)       0/43 (0%)       0/54 (0%)      |
|ADJUSTED (b)           |     13.5%           12.9%            6.3%          |      3.2%            0.0%            0.0%          |
|TERMINAL (d)           |     4/36 (11%)      2/31 (6%)       2/32 (6%)      |     1/31 (3%)       0/12 (0%)       0/26 (0%)      |
|FIRST INCIDENCE (DAYS) |      716             620             729 (T)       |      729 (T)         ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.233N        P=0.556         P=0.267N       |     P=0.319N        P=0.689N        P=0.535N       |
|INCIDENTAL TUMOR       |     P=0.255N        P=0.557         P=0.278N       |     P=0.319N        P=0.689N        P=0.535N       |
|LOGISTIC REGRESSION    |     P=0.241N        P=0.564         P=0.266N       |     P=0.319N        P=0.689N        P=0.535N       |
|COCHRAN-ARMITAGE       |     P=0.180N                                       |     P=0.290N                                       |
|FISHER EXACT           |                     P=0.629N        P=0.219N       |                     P=0.578N        P=0.522N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   2
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Adrenal Medulla                                                                                                                  |
|     Pheochromocytoma: Benign, Complex, Malignant, NOS                                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    22/58 (38%)     14/58 (24%)     13/58 (22%)     |     4/59 (7%)       1/43 (2%)       3/54 (6%)      |
|ADJUSTED (b)           |     49.1%           33.6%           34.6%          |     12.5%            8.3%           11.5%          |
|TERMINAL (d)           |    14/36 (39%)      5/31 (16%)      8/32 (25%)     |     3/31 (10%)      1/12 (8%)       3/26 (12%)     |
|FIRST INCIDENCE (DAYS) |      590             620             625           |      726             729 (T)         729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.108N        P=0.187N        P=0.130N       |     P=0.507N        P=0.470N        P=0.590N       |
|INCIDENTAL TUMOR       |     P=0.123N        P=0.136N        P=0.158N       |     P=0.512N        P=0.474N        P=0.598N       |
|LOGISTIC REGRESSION    |     P=0.120N        P=0.141N        P=0.127N       |     P=0.507N        P=0.525N        P=0.593N       |
|COCHRAN-ARMITAGE       |     P=0.040N*                                      |     P=0.459N                                       |
|FISHER EXACT           |                     P=0.080N        P=0.052N       |                     P=0.295N        P=0.550N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Brain                                                                                                                            |
|     Glioma Benign                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       0/27 (0%)       0/60 (0%)      |     0/60 (0%)       0/45 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      4.1%            0.0%            0.0%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     0/36 (0%)       0/1 (0%)        0/32 (0%)      |     0/31 (0%)       0/12 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      481             ---             ---           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.111N        P=0.260N        P=0.268N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.074N        P=0.271N        P=0.174N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.098N        P=0.347N        P=0.195N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.119N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.473N        P=0.248N       |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   3
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Brain                                                                                                                            |
|     Oligodendroglioma, Glioma, or Astrocytoma                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       1/27 (4%)       0/60 (0%)      |     1/60 (2%)       0/45 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      4.1%            2.7%            0.0%          |      2.7%            0.0%            2.8%          |
|TERMINAL (d)           |     0/36 (0%)       0/1 (0%)        0/32 (0%)      |     0/31 (0%)       0/12 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      481             714             ---           |      711             ---             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.167N        P=0.527N        P=0.268N       |     P=0.631         P=0.535N        P=0.724        |
|INCIDENTAL TUMOR       |     P=0.121N        P=0.567N        P=0.174N       |     P=0.606         P=0.536N        P=0.700        |
|LOGISTIC REGRESSION    |     P=0.160N        P=0.744         P=0.195N       |     P=0.621         P=0.635N        P=0.729        |
|COCHRAN-ARMITAGE       |     P=0.166N                                       |     P=0.662N                                       |
|FISHER EXACT           |                     P=0.677         P=0.248N       |                     P=0.571N        P=0.752N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/48 (0%)       4/23 (17%)      1/51 (2%)      |     2/39 (5%)       2/27 (7%)       3/53 (6%)      |
|ADJUSTED (b)           |      0.0%           52.5%            3.3%          |      7.1%            5.1%           10.0%          |
|TERMINAL (d)           |     0/31 (0%)       2/4 (50%)       1/30 (3%)      |     1/20 (5%)       0/11 (0%)       1/24 (4%)      |
|FIRST INCIDENCE (DAYS) |      ---             641             729 (T)       |      641             590             642           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.380         P=0.003 **      P=0.493        |     P=0.386         P=0.594         P=0.493        |
|INCIDENTAL TUMOR       |     P=0.375         P=0.003 **      P=0.493        |     P=0.420         P=0.590         P=0.521        |
|LOGISTIC REGRESSION    |     P=0.385         P=0.001 **      P=0.493        |     P=0.482         P=0.556         P=0.554        |
|COCHRAN-ARMITAGE       |     P=0.424                                        |     P=0.558                                        |
|FISHER EXACT           |                     P=0.009 **      P=0.515        |                     P=0.544         P=0.644        |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   4
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Clitoral/Preputial Gland                                                                                                         |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/48 (0%)       4/23 (17%)      1/51 (2%)      |     2/39 (5%)       2/27 (7%)       3/53 (6%)      |
|ADJUSTED (b)           |      0.0%           52.5%            3.3%          |      7.1%            5.1%           10.0%          |
|TERMINAL (d)           |     0/31 (0%)       2/4 (50%)       1/30 (3%)      |     1/20 (5%)       0/11 (0%)       1/24 (4%)      |
|FIRST INCIDENCE (DAYS) |      ---             641             729 (T)       |      641             590             642           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.380         P=0.003 **      P=0.493        |     P=0.386         P=0.594         P=0.493        |
|INCIDENTAL TUMOR       |     P=0.375         P=0.003 **      P=0.493        |     P=0.420         P=0.590         P=0.521        |
|LOGISTIC REGRESSION    |     P=0.385         P=0.001 **      P=0.493        |     P=0.482         P=0.556         P=0.554        |
|COCHRAN-ARMITAGE       |     P=0.424                                        |     P=0.558                                        |
|FISHER EXACT           |                     P=0.009 **      P=0.515        |                     P=0.544         P=0.644        |
|=================================================================================================================================|
|                                                                                                                                 |
|Islets, Pancreatic                                                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/59 (2%)       2/27 (7%)       1/60 (2%)      |     0/60 (0%)       0/44 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      2.8%           51.2%            3.1%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     1/36 (3%)       1/2 (50%)       1/32 (3%)      |     0/31 (0%)       0/12 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         676             729 (T)       |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.562         P=0.060         P=0.736        |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.563         P=0.055         P=0.736        |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.565         P=0.082         P=0.736        |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.605N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.231         P=0.748N       |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   5
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Islets, Pancreatic                                                                                                               |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/59 (3%)       2/27 (7%)       1/60 (2%)      |     0/60 (0%)       0/44 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      4.9%           51.2%            3.1%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     1/36 (3%)       1/2 (50%)       1/32 (3%)      |     0/31 (0%)       0/12 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      681             676             729 (T)       |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.453N        P=0.279         P=0.543N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.448N        P=0.260         P=0.537N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.449N        P=0.222         P=0.538N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.394N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.372         P=0.494N       |                       (e)             (e)          |
|=================================================================================================================================|
|                                                                                                                                 |
|Kidney: Renal Tubule                                                                                                             |
|     Nephroblastoma                                                                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       0/60 (0%)       0/59 (0%)      |     0/60 (0%)       2/59 (3%)       0/60 (0%)      |
|ADJUSTED (b)           |      0.0%            0.0%            0.0%          |      0.0%            4.0%            0.0%          |
|TERMINAL (d)           |     0/36 (0%)       0/33 (0%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      ---             ---             ---           |      ---             169             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |       (e)             (e)             (e)          |     P=0.637         P=0.205           (e)          |
|INCIDENTAL TUMOR       |       (e)             (e)             (e)          |     P=0.630N        P=0.335           (e)          |
|LOGISTIC REGRESSION    |       (e)             (e)             (e)          |     P=0.579N        P=0.402           (e)          |
|COCHRAN-ARMITAGE       |       (e)                                          |     P=0.668                                        |
|FISHER EXACT           |                       (e)             (e)          |                     P=0.244           (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   6
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Liver                                                                                                                            |
|     Hepatocellular Adenoma                                                                                                      |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       0/47 (0%)       0/60 (0%)      |     2/60 (3%)       1/51 (2%)       3/60 (5%)      |
|ADJUSTED (b)           |      2.8%            0.0%            0.0%          |      6.5%            5.6%           11.1%          |
|TERMINAL (d)           |     1/36 (3%)       0/20 (0%)       0/32 (0%)      |     2/31 (6%)       1/18 (6%)       3/27 (11%)     |
|FIRST INCIDENCE (DAYS) |      729 (T)         ---             ---           |      729 (T)         729 (T)         729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.302N        P=0.617N        P=0.523N       |     P=0.346         P=0.687N        P=0.436        |
|INCIDENTAL TUMOR       |     P=0.302N        P=0.617N        P=0.523N       |     P=0.346         P=0.687N        P=0.436        |
|LOGISTIC REGRESSION    |     P=0.302N        P=0.618N        P=0.524N       |     P=0.346         P=0.687N        P=0.436        |
|COCHRAN-ARMITAGE       |     P=0.277N                                       |     P=0.402                                        |
|FISHER EXACT           |                     P=0.561N        P=0.500N       |                     P=0.561N        P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Adenoma                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       0/60 (0%)       1/60 (2%)      |     3/60 (5%)       1/49 (2%)       0/60 (0%)      |
|ADJUSTED (b)           |      5.6%            0.0%            3.1%          |      9.1%            6.3%            0.0%          |
|TERMINAL (d)           |     2/36 (6%)       0/33 (0%)       1/32 (3%)      |     2/31 (6%)       1/16 (6%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         ---             729 (T)       |      719             729 (T)         ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.393N        P=0.258N        P=0.541N       |     P=0.091N        P=0.504N        P=0.147N       |
|INCIDENTAL TUMOR       |     P=0.393N        P=0.258N        P=0.541N       |     P=0.096N        P=0.510N        P=0.158N       |
|LOGISTIC REGRESSION    |     P=0.393N        P=0.258N        P=0.541N       |     P=0.094N        P=0.532N        P=0.150N       |
|COCHRAN-ARMITAGE       |     P=0.361N                                       |     P=0.067N                                       |
|FISHER EXACT           |                     P=0.248N        P=0.500N       |                     P=0.389N        P=0.122N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   7
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Lung                                                                                                                             |
|     Alveolar/Bronchiolar Carcinoma or Alveolar/Bronchiolar Adenoma                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       1/60 (2%)       1/60 (2%)      |     3/60 (5%)       1/49 (2%)       0/60 (0%)      |
|ADJUSTED (b)           |      5.6%            2.6%            3.1%          |      9.1%            6.3%            0.0%          |
|TERMINAL (d)           |     2/36 (6%)       0/33 (0%)       1/32 (3%)      |     2/31 (6%)       1/16 (6%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         705             729 (T)       |      719             729 (T)         ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.418N        P=0.532N        P=0.541N       |     P=0.091N        P=0.504N        P=0.147N       |
|INCIDENTAL TUMOR       |     P=0.415N        P=0.541N        P=0.541N       |     P=0.096N        P=0.510N        P=0.158N       |
|LOGISTIC REGRESSION    |     P=0.414N        P=0.529N        P=0.541N       |     P=0.094N        P=0.532N        P=0.150N       |
|COCHRAN-ARMITAGE       |     P=0.378N                                       |     P=0.067N                                       |
|FISHER EXACT           |                     P=0.500N        P=0.500N       |                     P=0.389N        P=0.122N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       0/60 (0%)       0/60 (0%)      |     1/60 (2%)       2/60 (3%)       0/60 (0%)      |
|ADJUSTED (b)           |      2.8%            0.0%            0.0%          |      1.8%            4.9%            0.0%          |
|TERMINAL (d)           |     1/36 (3%)       0/33 (0%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         ---             ---           |      507             606             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.287N        P=0.517N        P=0.523N       |     P=0.415N        P=0.443         P=0.545N       |
|INCIDENTAL TUMOR       |     P=0.287N        P=0.517N        P=0.523N       |     P=0.465N        P=0.414         P=0.638N       |
|LOGISTIC REGRESSION    |     P=0.287N        P=0.517N        P=0.524N       |     P=0.354N        P=0.516         P=0.453N       |
|COCHRAN-ARMITAGE       |     P=0.270N                                       |     P=0.361N                                       |
|FISHER EXACT           |                     P=0.500N        P=0.500N       |                     P=0.500         P=0.500N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   8
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |     0/60 (0%)       2/60 (3%)       2/60 (3%)      |
|ADJUSTED (b)           |      0.0%            0.0%            0.0%          |      0.0%            5.7%            7.4%          |
|TERMINAL (d)           |     0/36 (0%)       0/33 (0%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       2/27 (7%)      |
|FIRST INCIDENCE (DAYS) |      ---             ---             ---           |      ---             620             729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |       (e)             (e)             (e)          |     P=0.149         P=0.210         P=0.208        |
|INCIDENTAL TUMOR       |       (e)             (e)             (e)          |     P=0.141         P=0.196         P=0.208        |
|LOGISTIC REGRESSION    |       (e)             (e)             (e)          |     P=0.143         P=0.210         P=0.208        |
|COCHRAN-ARMITAGE       |       (e)                                          |     P=0.176                                        |
|FISHER EXACT           |                       (e)             (e)          |                     P=0.248         P=0.248        |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       0/60 (0%)       0/60 (0%)      |     1/60 (2%)       4/60 (7%)       2/60 (3%)      |
|ADJUSTED (b)           |      2.8%            0.0%            0.0%          |      1.8%           10.4%            7.4%          |
|TERMINAL (d)           |     1/36 (3%)       0/33 (0%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       2/27 (7%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         ---             ---           |      507             606             729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.287N        P=0.517N        P=0.523N       |     P=0.339         P=0.142         P=0.442        |
|INCIDENTAL TUMOR       |     P=0.287N        P=0.517N        P=0.523N       |     P=0.295         P=0.115         P=0.390        |
|LOGISTIC REGRESSION    |     P=0.287N        P=0.517N        P=0.524N       |     P=0.367         P=0.168         P=0.469        |
|COCHRAN-ARMITAGE       |     P=0.270N                                       |     P=0.407                                        |
|FISHER EXACT           |                     P=0.500N        P=0.500N       |                     P=0.182         P=0.500        |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE   9
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroadenoma                                                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     1/60 (2%)       2/60 (3%)       1/60 (2%)      |    25/60 (42%)     23/60 (38%)     12/60 (20%)     |
|ADJUSTED (b)           |      2.5%            6.1%            3.1%          |     57.0%           61.0%           35.8%          |
|TERMINAL (d)           |     0/36 (0%)       2/33 (6%)       1/32 (3%)      |    13/31 (42%)     13/27 (48%)      6/27 (22%)     |
|FIRST INCIDENCE (DAYS) |      711             729 (T)         729 (T)       |      553             603             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.586         P=0.471         P=0.739        |     P=0.049N*       P=0.470         P=0.047N*      |
|INCIDENTAL TUMOR       |     P=0.585         P=0.459         P=0.737        |     P=0.039N*       P=0.422         P=0.038N*      |
|LOGISTIC REGRESSION    |     P=0.587         P=0.470         P=0.738        |     P=0.036N*       P=0.429         P=0.035N*      |
|COCHRAN-ARMITAGE       |     P=0.622N                                       |     P=0.008N**                                     |
|FISHER EXACT           |                     P=0.500         P=0.752N       |                     P=0.426N        P=0.009N**     |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma or Adenoma                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       2/60 (3%)       1/60 (2%)      |    26/60 (43%)     25/60 (42%)     12/60 (20%)     |
|ADJUSTED (b)           |      5.2%            6.1%            3.1%          |     57.8%           63.0%           35.8%          |
|TERMINAL (d)           |     1/36 (3%)       2/33 (6%)       1/32 (3%)      |    13/31 (42%)     13/27 (48%)      6/27 (22%)     |
|FIRST INCIDENCE (DAYS) |      711             729 (T)         729 (T)       |      507             603             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.431N        P=0.663         P=0.536N       |     P=0.041N*       P=0.392         P=0.035N*      |
|INCIDENTAL TUMOR       |     P=0.432N        P=0.653         P=0.537N       |     P=0.032N*       P=0.322         P=0.030N*      |
|LOGISTIC REGRESSION    |     P=0.430N        P=0.664         P=0.538N       |     P=0.025N*       P=0.346         P=0.023N*      |
|COCHRAN-ARMITAGE       |     P=0.391N                                       |     P=0.005N**                                     |
|FISHER EXACT           |                     P=0.691N        P=0.500N       |                     P=0.500N        P=0.005N**     |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  10
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Mammary Gland                                                                                                                    |
|     Fibroma, Fibroadenoma, Carcinoma, or Adenoma                                                                                |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       2/60 (3%)       1/60 (2%)      |    26/60 (43%)     25/60 (42%)     14/60 (23%)     |
|ADJUSTED (b)           |      5.2%            6.1%            3.1%          |     57.8%           63.0%           42.0%          |
|TERMINAL (d)           |     1/36 (3%)       2/33 (6%)       1/32 (3%)      |    13/31 (42%)     13/27 (48%)      8/27 (30%)     |
|FIRST INCIDENCE (DAYS) |      711             729 (T)         729 (T)       |      507             603             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.431N        P=0.663         P=0.536N       |     P=0.084N        P=0.392         P=0.079N       |
|INCIDENTAL TUMOR       |     P=0.432N        P=0.653         P=0.537N       |     P=0.078N        P=0.322         P=0.079N       |
|LOGISTIC REGRESSION    |     P=0.430N        P=0.664         P=0.538N       |     P=0.063N        P=0.346         P=0.064N       |
|COCHRAN-ARMITAGE       |     P=0.391N                                       |     P=0.014N*                                      |
|FISHER EXACT           |                     P=0.691N        P=0.500N       |                     P=0.500N        P=0.016N*      |
|=================================================================================================================================|
|                                                                                                                                 |
|Pituitary Gland: Pars Distalis or Unspecified Site                                                                               |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    20/57 (35%)     16/59 (27%)     13/60 (22%)     |    30/60 (50%)     26/55 (47%)     20/60 (33%)     |
|ADJUSTED (b)           |     48.5%           37.8%           34.0%          |     65.8%           72.6%           55.8%          |
|TERMINAL (d)           |    14/34 (41%)      9/33 (27%)      8/32 (25%)     |    16/31 (52%)     14/23 (61%)     12/27 (44%)     |
|FIRST INCIDENCE (DAYS) |      599             451             533           |      553             471             337           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.156N        P=0.340N        P=0.177N       |     P=0.188N        P=0.407         P=0.193N       |
|INCIDENTAL TUMOR       |     P=0.098N        P=0.301N        P=0.139N       |     P=0.175N        P=0.292         P=0.160N       |
|LOGISTIC REGRESSION    |     P=0.107N        P=0.271N        P=0.137N       |     P=0.171N        P=0.280         P=0.176N       |
|COCHRAN-ARMITAGE       |     P=0.065N                                       |     P=0.040N*                                      |
|FISHER EXACT           |                     P=0.234N        P=0.080N       |                     P=0.458N        P=0.048N*      |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  11
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Pituitary Gland: Pars Distalis or Unspecified Site                                                                               |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    20/57 (35%)     16/59 (27%)     14/60 (23%)     |    31/60 (52%)     26/55 (47%)     21/60 (35%)     |
|ADJUSTED (b)           |     48.5%           37.8%           35.4%          |     68.0%           72.6%           57.1%          |
|TERMINAL (d)           |    14/34 (41%)      9/33 (27%)      8/32 (25%)     |    17/31 (55%)     14/23 (61%)     12/27 (44%)     |
|FIRST INCIDENCE (DAYS) |      599             451             533           |      553             471             337           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.213N        P=0.340N        P=0.240N       |     P=0.195N        P=0.460         P=0.202N       |
|INCIDENTAL TUMOR       |     P=0.144N        P=0.301N        P=0.201N       |     P=0.181N        P=0.355         P=0.169N       |
|LOGISTIC REGRESSION    |     P=0.150N        P=0.271N        P=0.190N       |     P=0.179N        P=0.341         P=0.187N       |
|COCHRAN-ARMITAGE       |     P=0.096N                                       |     P=0.041N*                                      |
|FISHER EXACT           |                     P=0.234N        P=0.116N       |                     P=0.388N        P=0.048N*      |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Keratoacanthoma                                                                                                             |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       0/60 (0%)       6/60 (10%)     |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      4.7%            0.0%           17.8%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     0/36 (0%)       0/33 (0%)       5/32 (16%)     |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      691             ---             703           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.049 *       P=0.264N        P=0.107        |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.048 *       P=0.276N        P=0.104        |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.046 *       P=0.249N        P=0.101        |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.061                                        |       (e)                                          |
|FISHER EXACT           |                     P=0.248N        P=0.136        |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  12
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Squamous Cell Carcinoma, Papilloma Squamous, or Papilloma                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       1/60 (2%)       0/60 (0%)      |     0/60 (0%)       0/60 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      5.6%            3.0%            0.0%          |      0.0%            0.0%            2.4%          |
|TERMINAL (d)           |     2/36 (6%)       1/33 (3%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         729 (T)         ---           |      ---             ---             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.163N        P=0.530N        P=0.264N       |     P=0.249           (e)           P=0.465        |
|INCIDENTAL TUMOR       |     P=0.163N        P=0.530N        P=0.264N       |     P=0.243           (e)           P=0.455        |
|LOGISTIC REGRESSION    |     P=0.163N        P=0.530N        P=0.264N       |     P=0.265           (e)           P=0.504        |
|COCHRAN-ARMITAGE       |     P=0.142N                                       |     P=0.270                                        |
|FISHER EXACT           |                     P=0.500N        P=0.248N       |                       (e)           P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Squamous Cell Papilloma                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       1/60 (2%)       0/60 (0%)      |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      5.6%            3.0%            0.0%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     2/36 (6%)       1/33 (3%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      729 (T)         729 (T)         ---           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.163N        P=0.530N        P=0.264N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.163N        P=0.530N        P=0.264N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.163N        P=0.530N        P=0.264N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.142N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.500N        P=0.248N       |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  13
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Trichoepithelioma                                                                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       0/60 (0%)       0/60 (0%)      |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      5.4%            0.0%            0.0%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     1/36 (3%)       0/33 (0%)       0/32 (0%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      723             ---             ---           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.110N        P=0.259N        P=0.266N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.111N        P=0.270N        P=0.263N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.107N        P=0.257N        P=0.261N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.096N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.248N        P=0.248N       |                       (e)             (e)          |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Trichoepithelioma, Basal Cell Carcinoma, or Basal Cell Adenoma                                                              |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       0/60 (0%)       1/60 (2%)      |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      8.1%            0.0%            3.1%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     2/36 (6%)       0/33 (0%)       1/32 (3%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      723             ---             729 (T)       |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.205N        P=0.139N        P=0.349N       |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.204N        P=0.145N        P=0.346N       |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.200N        P=0.136N        P=0.343N       |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.176N                                       |       (e)                                          |
|FISHER EXACT           |                     P=0.122N        P=0.309N       |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  14
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin                                                                                                                             |
|     Trichoepithelioma, Kertatocanthoma, Squamous Cell Carcinoma,                                                                |
|     Basal Cell Carcinoma or Adenoma, Papilloma Squamous, or Papilloma                                                           |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     7/60 (12%)      1/60 (2%)       7/60 (12%)     |     0/60 (0%)       0/60 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |     17.5%            3.0%           20.9%          |      0.0%            0.0%            2.4%          |
|TERMINAL (d)           |     4/36 (11%)      1/33 (3%)       6/32 (19%)     |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      691             729 (T)         703           |      ---             ---             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.490         P=0.047N*       P=0.523        |     P=0.249           (e)           P=0.465        |
|INCIDENTAL TUMOR       |     P=0.493         P=0.049N*       P=0.527        |     P=0.243           (e)           P=0.455        |
|LOGISTIC REGRESSION    |     P=0.493         P=0.042N*       P=0.527        |     P=0.265           (e)           P=0.504        |
|COCHRAN-ARMITAGE       |     P=0.566                                        |     P=0.270                                        |
|FISHER EXACT           |                     P=0.031N*       P=0.611N       |                       (e)           P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Fibroma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       3/60 (5%)       2/60 (3%)      |     0/60 (0%)       0/60 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      6.6%            7.4%            6.3%          |      0.0%            0.0%            2.9%          |
|TERMINAL (d)           |     1/36 (3%)       1/33 (3%)       2/32 (6%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      542             451             729 (T)       |      ---             ---             678           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.469N        P=0.624         P=0.556N       |     P=0.246           (e)           P=0.463        |
|INCIDENTAL TUMOR       |     P=0.365N        P=0.626         P=0.479N       |     P=0.233           (e)           P=0.443        |
|LOGISTIC REGRESSION    |     P=0.421N        P=0.643N        P=0.530N       |     P=0.252           (e)           P=0.473        |
|COCHRAN-ARMITAGE       |     P=0.412N                                       |     P=0.270                                        |
|FISHER EXACT           |                     P=0.660N        P=0.500N       |                       (e)           P=0.500        |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  15
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Neurofibroma or Fibroma                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       4/60 (7%)       2/60 (3%)      |     0/60 (0%)       0/60 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      6.6%            9.1%            6.3%          |      0.0%            0.0%            2.9%          |
|TERMINAL (d)           |     1/36 (3%)       1/33 (3%)       2/32 (6%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      542             451             729 (T)       |      ---             ---             678           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.477N        P=0.463         P=0.556N       |     P=0.246           (e)           P=0.463        |
|INCIDENTAL TUMOR       |     P=0.329N        P=0.451         P=0.479N       |     P=0.233           (e)           P=0.443        |
|LOGISTIC REGRESSION    |     P=0.403N        P=0.544         P=0.530N       |     P=0.252           (e)           P=0.473        |
|COCHRAN-ARMITAGE       |     P=0.417N                                       |     P=0.270                                        |
|FISHER EXACT           |                     P=0.500         P=0.500N       |                       (e)           P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Neurofibrosarcoma, Fibrosarcoma, Sarcoma,                                                                                   |
|     Neurofibroma, or Fibroma                                                                                                    |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     3/60 (5%)       4/60 (7%)       4/60 (7%)      |     0/60 (0%)       0/60 (0%)       2/60 (3%)      |
|ADJUSTED (b)           |      6.6%            9.1%           12.5%          |      0.0%            0.0%            6.1%          |
|TERMINAL (d)           |     1/36 (3%)       1/33 (3%)       4/32 (13%)     |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      542             451             729 (T)       |      ---             ---             678           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.363         P=0.463         P=0.434        |     P=0.085           (e)           P=0.210        |
|INCIDENTAL TUMOR       |     P=0.493         P=0.451         P=0.499        |     P=0.068           (e)           P=0.173        |
|LOGISTIC REGRESSION    |     P=0.417         P=0.544         P=0.450        |     P=0.081           (e)           P=0.200        |
|COCHRAN-ARMITAGE       |     P=0.424                                        |     P=0.096                                        |
|FISHER EXACT           |                     P=0.500         P=0.500        |                       (e)           P=0.248        |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  16
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Skin: Subcutaneous Tissue                                                                                                        |
|     Neurofibrosarcoma, Fibrosarcoma, or Sarcoma                                                                                 |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     0/60 (0%)       0/60 (0%)       2/60 (3%)      |     0/60 (0%)       0/60 (0%)       1/60 (2%)      |
|ADJUSTED (b)           |      0.0%            0.0%            6.3%          |      0.0%            0.0%            3.2%          |
|TERMINAL (d)           |     0/36 (0%)       0/33 (0%)       2/32 (6%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      ---             ---             729 (T)       |      ---             ---             720           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.085           (e)           P=0.213        |     P=0.259           (e)           P=0.482        |
|INCIDENTAL TUMOR       |     P=0.085           (e)           P=0.213        |     P=0.233           (e)           P=0.443        |
|LOGISTIC REGRESSION    |     P=0.085           (e)           P=0.213        |     P=0.247           (e)           P=0.464        |
|COCHRAN-ARMITAGE       |     P=0.096                                        |     P=0.270                                        |
|FISHER EXACT           |                       (e)           P=0.248        |                       (e)           P=0.500        |
|=================================================================================================================================|
|                                                                                                                                 |
|Testes                                                                                                                           |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    56/60 (93%)     48/58 (83%)     48/60 (80%)     |                                                    |
|ADJUSTED (b)           |    100.0%           97.9%           97.9%          |                                                    |
|TERMINAL (d)           |    36/36 (100%)    30/31 (97%)     31/32 (97%)     |                                                    |
|FIRST INCIDENCE (DAYS) |      364             575             431           |                                                    |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.406N        P=0.465N        P=0.436N       |                                                    |
|INCIDENTAL TUMOR       |     P=0.189N        P=0.153N        P=0.196N       |                                                    |
|LOGISTIC REGRESSION    |     P=0.248N        P=0.161N        P=0.265N       |                                                    |
|COCHRAN-ARMITAGE       |     P=0.026N*                                      |                                                    |
|FISHER EXACT           |                     P=0.067N        P=0.029N*      |                                                    |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  17
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Adenoma                                                                                                                     |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     7/60 (12%)      7/60 (12%)      5/58 (9%)      |     5/59 (8%)       2/45 (4%)       5/60 (8%)      |
|ADJUSTED (b)           |     19.4%           16.7%           15.1%          |     14.5%           10.7%           17.2%          |
|TERMINAL (d)           |     7/36 (19%)      3/33 (9%)       4/32 (13%)     |     4/31 (13%)      1/13 (8%)       4/27 (15%)     |
|FIRST INCIDENCE (DAYS) |      729 (T)         598             719           |      494             723             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.411N        P=0.548         P=0.461N       |     P=0.473         P=0.531N        P=0.533        |
|INCIDENTAL TUMOR       |     P=0.439N        P=0.607         P=0.474N       |     P=0.442         P=0.546N        P=0.496        |
|LOGISTIC REGRESSION    |     P=0.427N        P=0.573         P=0.457N       |     P=0.454         P=0.495N        P=0.519        |
|COCHRAN-ARMITAGE       |     P=0.351N                                       |     P=0.560N                                       |
|FISHER EXACT           |                     P=0.611N        P=0.405N       |                     P=0.345N        P=0.618N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Carcinoma                                                                                                                   |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     6/60 (10%)      2/60 (3%)       2/58 (3%)      |     4/59 (7%)       2/45 (4%)       3/60 (5%)      |
|ADJUSTED (b)           |     15.5%            5.9%            6.3%          |     12.9%           10.7%           11.1%          |
|TERMINAL (d)           |     4/36 (11%)      1/33 (3%)       2/32 (6%)      |     4/31 (13%)      1/13 (8%)       3/27 (11%)     |
|FIRST INCIDENCE (DAYS) |      706             723             729 (T)       |      729 (T)         723             729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.111N        P=0.170N        P=0.178N       |     P=0.501N        P=0.661         P=0.577N       |
|INCIDENTAL TUMOR       |     P=0.121N        P=0.178N        P=0.193N       |     P=0.507N        P=0.654         P=0.577N       |
|LOGISTIC REGRESSION    |     P=0.107N        P=0.163N        P=0.175N       |     P=0.499N        P=0.637         P=0.577N       |
|COCHRAN-ARMITAGE       |     P=0.088N                                       |     P=0.412N                                       |
|FISHER EXACT           |                     P=0.136N        P=0.147N       |                     P=0.475N        P=0.491N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  18
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Thyroid Gland: C-Cell                                                                                                            |
|     Carcinoma or Adenoma                                                                                                        |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |                                                    |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    13/60 (22%)      9/60 (15%)      6/58 (10%)     |     9/59 (15%)      3/45 (7%)       8/60 (13%)     |
|ADJUSTED (b)           |     34.0%           21.8%           18.1%          |     27.1%           18.1%           28.0%          |
|TERMINAL (d)           |    11/36 (31%)      4/33 (12%)      5/32 (16%)     |     8/31 (26%)      2/13 (15%)      7/27 (26%)     |
|FIRST INCIDENCE (DAYS) |      706             598             719           |      494             723             663           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.090N        P=0.316N        P=0.106N       |     P=0.540         P=0.397N        P=0.584        |
|INCIDENTAL TUMOR       |     P=0.101N        P=0.281N        P=0.116N       |     P=0.514         P=0.409N        P=0.554        |
|LOGISTIC REGRESSION    |     P=0.092N        P=0.292N        P=0.098N       |     P=0.509         P=0.326N        P=0.547        |
|COCHRAN-ARMITAGE       |     P=0.059N                                       |     P=0.431N                                       |
|FISHER EXACT           |                     P=0.240N        P=0.077N       |                     P=0.147N        P=0.485N       |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Polyp Stromal                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    |    11/60 (18%)      8/60 (13%)      9/60 (15%)     |
|ADJUSTED (b)           |                                                    |     32.8%           22.7%           28.7%          |
|TERMINAL (d)           |                                                    |     9/31 (29%)      3/27 (11%)      6/27 (22%)     |
|FIRST INCIDENCE (DAYS) |                                                    |      663             541             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |     P=0.489N        P=0.429N        P=0.539N       |
|INCIDENTAL TUMOR       |                                                    |     P=0.541N        P=0.453N        P=0.572N       |
|LOGISTIC REGRESSION    |                                                    |     P=0.524N        P=0.453N        P=0.584N       |
|COCHRAN-ARMITAGE       |                                                    |     P=0.353N                                       |
|FISHER EXACT           |                                                    |                     P=0.309N        P=0.404N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  19
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Sarcoma Stromal                                                                                                             |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    |     0/60 (0%)       1/60 (2%)       2/60 (3%)      |
|ADJUSTED (b)           |                                                    |      0.0%            3.0%            7.4%          |
|TERMINAL (d)           |                                                    |     0/31 (0%)       0/27 (0%)       2/27 (7%)      |
|FIRST INCIDENCE (DAYS) |                                                    |      ---             695             729 (T)       |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |     P=0.121         P=0.457         P=0.208        |
|INCIDENTAL TUMOR       |                                                    |     P=0.117         P=0.464         P=0.208        |
|LOGISTIC REGRESSION    |                                                    |     P=0.116         P=0.469         P=0.208        |
|COCHRAN-ARMITAGE       |                                                    |     P=0.142                                        |
|FISHER EXACT           |                                                    |                     P=0.500         P=0.248        |
|=================================================================================================================================|
|                                                                                                                                 |
|Uterus                                                                                                                           |
|     Sarcoma Stromal or Polyp Stromal                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |                                                    |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |                                                    |    11/60 (18%)      9/60 (15%)     11/60 (18%)     |
|ADJUSTED (b)           |                                                    |     32.8%           25.0%           35.5%          |
|TERMINAL (d)           |                                                    |     9/31 (29%)      3/27 (11%)      8/27 (30%)     |
|FIRST INCIDENCE (DAYS) |                                                    |      663             541             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |                                                    |     P=0.401         P=0.536N        P=0.448        |
|INCIDENTAL TUMOR       |                                                    |     P=0.348         P=0.562N        P=0.417        |
|LOGISTIC REGRESSION    |                                                    |     P=0.362         P=0.562N        P=0.402        |
|COCHRAN-ARMITAGE       |                                                    |     P=0.548                                        |
|FISHER EXACT           |                                                    |                     P=0.404N        P=0.593N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  20
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Leukemia: Lymphocytic, Monocytic, Mononuclear,                                                                              |
|     or Undifferentiated                                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    13/60 (22%)     11/60 (18%)     12/60 (20%)     |    11/60 (18%)      6/60 (10%)      8/60 (13%)     |
|ADJUSTED (b)           |     27.8%           28.1%           28.8%          |     26.6%           19.4%           24.5%          |
|TERMINAL (d)           |     6/36 (17%)      6/33 (18%)      5/32 (16%)     |     5/31 (16%)      4/27 (15%)      4/27 (15%)     |
|FIRST INCIDENCE (DAYS) |      549             641             515           |      494             599             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.508         P=0.506N        P=0.547        |     P=0.384N        P=0.252N        P=0.450N       |
|INCIDENTAL TUMOR       |     P=0.522         P=0.442N        P=0.557        |     P=0.427N        P=0.254N        P=0.511N       |
|LOGISTIC REGRESSION    |     P=0.544N        P=0.448N        P=0.570N       |     P=0.381N        P=0.229N        P=0.442N       |
|COCHRAN-ARMITAGE       |     P=0.455N                                       |     P=0.255N                                       |
|FISHER EXACT           |                     P=0.410N        P=0.500N       |                     P=0.148N        P=0.309N       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Mesothelioma Benign, Malignant, NOS                                                                                         |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |     2/60 (3%)       3/60 (5%)       4/60 (7%)      |     0/60 (0%)       0/60 (0%)       0/60 (0%)      |
|ADJUSTED (b)           |      4.6%            7.5%           10.5%          |      0.0%            0.0%            0.0%          |
|TERMINAL (d)           |     1/36 (3%)       1/33 (3%)       2/32 (6%)      |     0/31 (0%)       0/27 (0%)       0/27 (0%)      |
|FIRST INCIDENCE (DAYS) |      603             634             570           |      ---             ---             ---           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.226         P=0.463         P=0.292        |       (e)             (e)             (e)          |
|INCIDENTAL TUMOR       |     P=0.201         P=0.525         P=0.264        |       (e)             (e)             (e)          |
|LOGISTIC REGRESSION    |     P=0.243         P=0.497         P=0.314        |       (e)             (e)             (e)          |
|COCHRAN-ARMITAGE       |     P=0.265                                        |       (e)                                          |
|FISHER EXACT           |                     P=0.500         P=0.340        |                       (e)             (e)          |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  21
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Benign Tumors                                                                                                               |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    59/60 (98%)     56/60 (93%)     51/60 (85%)     |    52/60 (87%)     42/60 (70%)     34/60 (57%)     |
|ADJUSTED (b)           |    100.0%          100.0%          100.0%          |     98.1%           91.2%           82.8%          |
|TERMINAL (d)           |    36/36 (100%)    33/33 (100%)    32/32 (100%)    |    30/31 (97%)     23/27 (85%)     20/27 (74%)     |
|FIRST INCIDENCE (DAYS) |      364             451             431           |      479             471             337           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.440N        P=0.455         P=0.461N       |     P=0.052N        P=0.377N        P=0.053N       |
|INCIDENTAL TUMOR       |     P=0.027N*       P=0.362N        P=0.079N       |     P=0.008N**      P=0.372N        P=0.009N**     |
|LOGISTIC REGRESSION    |     P=0.065N        P=0.490N        P=0.142N       |     P=0.004N**      P=0.355N        P=0.007N**     |
|COCHRAN-ARMITAGE       |     P=0.005N**                                     |     P<0.001N**                                     |
|FISHER EXACT           |                     P=0.182N        P=0.008N**     |                     P=0.022N*       P<0.001N**     |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant Tumors                                                                                                            |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    30/60 (50%)     28/60 (47%)     21/60 (35%)     |    21/60 (35%)     15/60 (25%)     18/60 (30%)     |
|ADJUSTED (b)           |     57.4%           56.0%           49.5%          |     47.2%           40.1%           52.0%          |
|TERMINAL (d)           |    15/36 (42%)     12/33 (36%)     12/32 (38%)     |    10/31 (32%)      7/27 (26%)     11/27 (41%)     |
|FIRST INCIDENCE (DAYS) |      145             365             515           |      494             169             606           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.204N        P=0.536         P=0.212N       |     P=0.524N        P=0.348N        P=0.568N       |
|INCIDENTAL TUMOR       |     P=0.108N        P=0.386N        P=0.126N       |     P=0.507         P=0.303N        P=0.504        |
|LOGISTIC REGRESSION    |     P=0.108N        P=0.425N        P=0.101N       |     P=0.512N        P=0.272N        P=0.562        |
|COCHRAN-ARMITAGE       |     P=0.059N                                       |     P=0.309N                                       |
|FISHER EXACT           |                     P=0.428N        P=0.070N       |                     P=0.160N        P=0.348N       |
|=================================================================================================================================|
 
         DATE: 09/05/94                     EXPERIMENT: 05041 TEST: 01                                                 PAGE  22
                           STATISTICAL ANALYSIS OF PRIMARY TUMORS IN RATS(FISCHER344) -- SUCCINIC ANHYDRIDE
 
                                                 TERMINAL SACRIFICE AT 105 WEEKS
 
|=================================================================================================================================|
|                       |                                                    |                                                    |
|                       |                       MALES                        |                      FEMALES                       |
|                       |                                                    |                                                    |
|DOSE                   |      CONTROL         50MG/KG         100MG/KG      |      CONTROL         50MG/KG         100MG/KG      |
|                       |      MALE            LOW MALE        HIGHMALE      |      FEMALE          LOW FEM         HIGHFEM       |
|=================================================================================================================================|
|                                                                                                                                 |
|All Organs                                                                                                                       |
|     Malignant and Benign Tumors                                                                                                 |
|                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------|
|TUMOR RATES            |       #               #               #            |       #               #               #            |
|-----------            |                                                    |                                                    |
|OVERALL (a)            |    60/60 (100%)    57/60 (95%)     52/60 (87%)     |    55/60 (92%)     47/60 (78%)     39/60 (65%)     |
|ADJUSTED (b)           |    100.0%          100.0%          100.0%          |     98.2%           95.9%           90.6%          |
|TERMINAL (d)           |    36/36 (100%)    33/33 (100%)    32/32 (100%)    |    30/31 (97%)     25/27 (93%)     23/27 (85%)     |
|FIRST INCIDENCE (DAYS) |      145             365             431           |      479             169             337           |
|-----------------------|                                                    |                                                    |
|STATISTICAL TESTS (f)  |                                                    |                                                    |
|-----------------------|                                                    |                                                    |
|LIFE TABLE             |     P=0.446N        P=0.455         P=0.466N       |     P=0.118N        P=0.534N        P=0.120N       |
|INCIDENTAL TUMOR       |     P=0.009N**      P=0.215N        P=0.028N*      |     P=0.012N*       P=0.673         P=0.017N*      |
|LOGISTIC REGRESSION    |     P=0.013N*       P=0.176N        P=0.041N*      |     P=0.005N**      P=0.659         P=0.016N*      |
|COCHRAN-ARMITAGE       |     P=0.002N**                                     |     P<0.001N**                                     |
|FISHER EXACT           |                     P=0.122N        P=0.003N**     |                     P=0.036N*       P<0.001N**     |
|=================================================================================================================================|
 
 (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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