NTP STATISTICAL ANALYSIS OF NON-NEOPLASTIC LESIONS REPORT: PEIRPT10 LAB: Battelle Columbus ACETAMINOPHEN (4-HYDROXYACETANILIDE) DATE: 08/18/04 EXPERIMENT: 55801 TEST: 06 TIME: 10:43:19 TEST TYPE: ACUTE CAGES FROM 0000 TO LAST CAGE PAGE: 1 CONT: N01-ES-65406 ROUTE: GAVAGE NTP C#: 55801E PATHOLOGIST: MISSING CAS: 103-90-2 ------------------------------------------------------------------------------------------------------------------------------------ FINAL #1 RATS/48 HOURS DAY REASONS FOR REMOVAL: ALL REMOVAL DATE RANGE: ALL TREATMENT GROUPS: INCLUDE 004 0 MG/KG 48 HR INCLUDE 008 50 MG/KG48 HR INCLUDE 012 150MG/KG48 HR INCLUDE 016 1500MG/K48 HR INCLUDE 020 2000MG/K48 HR NTP STATISTICAL ANALYSIS OF NON-NEOPLASTIC LESIONS REPORT: PEIRPT10 LAB: Battelle Columbus ACETAMINOPHEN (4-HYDROXYACETANILIDE) DATE: 08/18/04 EXPERIMENT: 55801 TEST: 06 TIME: 10:43:19 TEST TYPE: ACUTE CAGES FROM 0000 TO LAST CAGE CONT: N01-ES-65406 ROUTE: GAVAGE NTP C#: 55801E PATHOLOGIST: MISSING CAS: 103-90-2 SUMMARY OF STATISTICALLY SIGNIFICANT (P<=.05) RESULTS IN THE ANALYSIS OF ACETAMINOPHEN (4-HYDROXYACETANILI =============================================================== Male Rats ------------ Organ Morphology ----- ---------- Liver, Left Lobe: Centrilobular Infiltration Cellular Mononuclear Cell Necrosis Liver, Left Lobe: Hepatocyte Degeneration Regeneration Liver, Left Lobe: Sinusoid Congestion Liver, Median Lobe: Centrilobular Infiltration Cellular Mononuclear Cell Necrosis Liver, Median Lobe: Hepatocyte Degeneration Regeneration Liver, Median Lobe: Sinusoid Congestion =============================================================== Date: 08/18/04 EXPERIMENT: 55801 TEST: 06 Page 1 Statistical Analysis of Non-neoplastic Lesions in Rats(FISCHER 344) - ACETAMINOPHEN (4-HYDROXYACETANILI Terminal Sacrifice at 1 weeks |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Left Lobe: Centrilobular | | Infiltration Cellular Mononuclear Cell | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 6/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 100.0% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.003 ** P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.003 ** P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Left Lobe: Centrilobular | | Necrosis | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 6/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 100.0% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.003 ** P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.003 ** P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| Date: 08/18/04 EXPERIMENT: 55801 TEST: 06 Page 2 Statistical Analysis of Non-neoplastic Lesions in Rats(FISCHER 344) - ACETAMINOPHEN (4-HYDROXYACETANILI Terminal Sacrifice at 1 weeks |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Left Lobe: Hepatocyte | | Degeneration | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 4/6 (67%) 3/6 (50%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 4/6.00 3/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 66.7% 50.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 4/6 (67%) 3/6 (50%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.039 * P=0.101 | |POLY 3 | P<0.001 ** (e) (e) P=0.009 ** P=0.068 | |POLY 1.5 | P<0.001 ** (e) (e) P=0.009 ** P=0.068 | |POLY 6 | P<0.001 ** (e) (e) P=0.009 ** P=0.068 | |LOGISTIC REGRESSION| (e) (e) (e) P=0.039 * P=0.101 | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P=0.030 * P=0.091 | |ORDER RESTRICTED | P=0.002 ** (e) (e) (e) (e) | |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Left Lobe: Hepatocyte | | Regeneration | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 5/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 83.3% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.012 * P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.012 * P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P=0.008 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| Date: 08/18/04 EXPERIMENT: 55801 TEST: 06 Page 3 Statistical Analysis of Non-neoplastic Lesions in Rats(FISCHER 344) - ACETAMINOPHEN (4-HYDROXYACETANILI Terminal Sacrifice at 1 weeks |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Left Lobe: Sinusoid | | Congestion | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 2/6 (33%) 3/6 (50%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 2/6.00 3/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 33.3% 50.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 2/6 (33%) 3/6 (50%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P=0.004 ** (e) (e) P=0.229 P=0.101 | |POLY 3 | P<0.001 ** (e) (e) P=0.215 P=0.068 | |POLY 1.5 | P<0.001 ** (e) (e) P=0.215 P=0.068 | |POLY 6 | P<0.001 ** (e) (e) P=0.215 P=0.068 | |LOGISTIC REGRESSION| (e) (e) (e) P=0.229 P=0.101 | |COCH-ARM / FISHERS | P=0.004 ** (e) (e) P=0.227 P=0.091 | |ORDER RESTRICTED | P=0.007 ** (e) (e) (e) (e) | |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Median Lobe: Centrilobular | | Infiltration Cellular Mononuclear Cell | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 6/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 100.0% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.003 ** P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.003 ** P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| Date: 08/18/04 EXPERIMENT: 55801 TEST: 06 Page 4 Statistical Analysis of Non-neoplastic Lesions in Rats(FISCHER 344) - ACETAMINOPHEN (4-HYDROXYACETANILI Terminal Sacrifice at 1 weeks |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Median Lobe: Centrilobular | | Necrosis | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 6/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 100.0% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 6/6 (100%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.003 ** P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.003 ** P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Median Lobe: Hepatocyte | | Degeneration | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 3/6 (50%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 5/6.00 3/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 83.3% 50.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 3/6 (50%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.012 * P=0.101 | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |LOGISTIC REGRESSION| (e) (e) (e) P=0.012 * P=0.101 | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P=0.008 ** P=0.091 | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| Date: 08/18/04 EXPERIMENT: 55801 TEST: 06 Page 5 Statistical Analysis of Non-neoplastic Lesions in Rats(FISCHER 344) - ACETAMINOPHEN (4-HYDROXYACETANILI Terminal Sacrifice at 1 weeks |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Median Lobe: Hepatocyte | | Regeneration | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 6/6 (100%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 5/6.00 6/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 83.3% 100.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 6/6 (100%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.012 * P=0.003 ** | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P<0.001 ** | |LOGISTIC REGRESSION| (e) (e) (e) P=0.012 * P=0.003 ** | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P=0.008 ** P<0.001 ** | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| | | | | | Males | |Dose | 0 MG/KG 50 MG/KG 150MG/KG 1500MG/K 2000MG/K | | | 48 HR 48 HR 48 HR 48 HR 48 HR | |=================================================================================================================================| | | |Liver, Median Lobe: Sinusoid | | Congestion | | | | | |---------------------------------------------------------------------------------------------------------------------------------| |LESION RATES | | |----------- | | |OVERALL (a) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 3/6 (50%) | |POLY-3 RATE (b) | 0/6.00 0/6.00 0/6.00 5/6.00 3/6.00 | |POLY-3 PERCENT (g) | 0.0% 0.0% 0.0% 83.3% 50.0% | |TERMINAL (d) | 0/6 (0%) 0/6 (0%) 0/6 (0%) 5/6 (83%) 3/6 (50%) | |FIRST INCIDENCE | --- --- --- 3 (T) 3 (T) | |-------------------| | |STATISTICAL TESTS | | |-------------------| | |LIFE TABLE | P<0.001 ** (e) (e) P=0.012 * P=0.101 | |POLY 3 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |POLY 1.5 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |POLY 6 | P<0.001 ** (e) (e) P<0.001 ** P=0.068 | |LOGISTIC REGRESSION| (e) (e) (e) P=0.012 * P=0.101 | |COCH-ARM / FISHERS | P<0.001 ** (e) (e) P=0.008 ** P=0.091 | |ORDER RESTRICTED | P<0.001 ** (e) (e) (e) (e) | |=================================================================================================================================| (a) Number of tumor-bearing animals / number of animals examined at site. (b) Number of tumor-bearing animals / Poly-3 number (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. Logistic regression is an alternative method for analyzing the incidence of non-fatal tumors. The Cochran-Armitage and Fishers 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. (g) Poly-3 adjusted lifetime tumor incidence. (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).