TDMS Study 05109-12 Pathology Tables
INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) TRIETHANOLAMINE NTP Experiment-Test: 05109-12 Report: PEIRPT03 Study Type: CHRONIC Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 Facility: Battelle Columbus Laboratory Chemical CAS #: 102-71-6 Lock Date: 08/21/92 Cage Range: All Reasons For Removal: All Removal Date Range: All Treatment Groups: Include All a Number of animals examined microscopically at site and number of animals with lesion Page 1 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE FEMALE 0 MG/KG 100 300 1000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ DISPOSITION SUMMARY Animals Initially In Study 60 60 60 60 Scheduled Sacrifice 10 10 10 10 Early Deaths Moribund Sacrifice 7 4 5 11 Natural Death 4 6 7 2 Survivors Terminal Sacrifice 38 40 38 37 Natural Death 1 Animals Examined Microscopically 60 60 60 60 ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM Intestine Large, Colon (60) (60) (60) (60) Inflammation, Chronic Active 1 (2%) Intestine Small, Jejunum (60) (60) (60) (60) Peyer's Patch, Hyperplasia, Lymphoid 2 (3%) Liver (60) (60) (60) (60) Basophilic Focus 2 (3%) 2 (3%) 1 (2%) Clear Cell Focus 1 (2%) 1 (2%) 1 (2%) Congestion 1 (2%) Cytoplasmic Alteration 1 (2%) Eosinophilic Focus 11 (18%) 10 (17%) 18 (30%) 17 (28%) Fatty Change 1 (2%) Hematopoietic Cell Proliferation 1 (2%) Hepatodiaphragmatic Nodule 1 (2%) Hypertrophy 1 (2%) Infiltration Cellular, Lymphocyte 2 (3%) Inflammation, Chronic Active 1 (2%) 1 (2%) Karyomegaly 1 (2%) Leukocytosis 1 (2%) Necrosis 2 (3%) 3 (5%) 2 (3%) 1 (2%) Kupffer Cell, Hyperplasia 1 (2%) Mesentery (2) (5) (5) (5) Fat, Infiltration Cellular, Lymphocyte 1 (20%) Fat, Inflammation, Chronic 2 (100%) 4 (80%) 3 (60%) 3 (60%) Pancreas (60) (60) (60) (60) Cyst 1 (2%) Inflammation, Chronic Active 1 (2%) 1 (2%) Acinus, Atrophy 4 (7%) 2 (3%) 1 (2%) Artery, Inflammation, Chronic 1 (2%) Duct, Cyst 1 (2%) Stomach, Forestomach (60) (60) (60) (60) Acanthosis 1 (2%) 1 (2%) 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 2 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE FEMALE 0 MG/KG 100 300 1000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM - CONT Stomach, Glandular (60) (60) (60) (60) Hyperplasia 1 (2%) 1 (2%) 1 (2%) Inflammation, Chronic Active 1 (2%) Pigmentation 1 (2%) 1 (2%) Ulcer 1 (2%) ____________________________________________________________________________________________________________________________________ CARDIOVASCULAR SYSTEM Heart (60) (60) (60) (60) Artery, Thrombosis 1 (2%) Coronary Artery, Inflammation, Chronic 1 (2%) ____________________________________________________________________________________________________________________________________ ENDOCRINE SYSTEM Adrenal Cortex (60) (59) (60) (60) Hyperplasia 1 (2%) Hypertrophy 3 (5%) 2 (3%) 3 (5%) 1 (2%) Infiltration Cellular, Lymphocyte 1 (2%) Necrosis 1 (2%) Capsule, Accessory Adrenal Cortical Nodule 2 (3%) 2 (3%) Capsule, Cyst 1 (2%) 1 (2%) Capsule, Spindle Cell, Hyperplasia 1 (2%) 1 (2%) Adrenal Medulla (60) (60) (60) (60) Cyst 1 (2%) Hyperplasia 1 (2%) 3 (5%) 3 (5%) Pituitary Gland (54) (59) (59) (59) Pars Distalis, Angiectasis 1 (2%) Pars Distalis, Cyst 1 (2%) 2 (3%) 1 (2%) Pars Distalis, Hyperplasia 3 (6%) 7 (12%) 8 (14%) 5 (8%) Pars Intermedia, Hyperplasia 1 (2%) Rathke's Cleft, Cyst 1 (2%) Rathke's Cleft, Hemorrhage 1 (2%) Thyroid Gland (60) (60) (60) (60) Infiltration Cellular, Lymphocyte 1 (2%) Inflammation, Chronic Active 1 (2%) Follicle, Cyst 1 (2%) 2 (3%) Follicular Cell, Hyperplasia 23 (38%) 20 (33%) 18 (30%) 27 (45%) ____________________________________________________________________________________________________________________________________ GENERAL BODY SYSTEM None ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 3 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE FEMALE 0 MG/KG 100 300 1000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ GENITAL SYSTEM Clitoral Gland (58) (58) (56) (58) Inflammation, Chronic 1 (2%) Duct, Ectasia 3 (5%) 1 (2%) 2 (4%) 3 (5%) Ovary (59) (60) (59) (60) Atrophy 34 (58%) 37 (62%) 34 (58%) 29 (48%) Cyst 1 (2%) Thrombosis 2 (3%) 2 (3%) 1 (2%) Follicle, Cyst 15 (25%) 19 (32%) 18 (31%) 14 (23%) Follicle, Cyst, Multiple 1 (2%) Periovarian Tissue, Cyst 1 (2%) 1 (2%) Periovarian Tissue, Infiltration Cellular, Lymphocyte 1 (2%) Periovarian Tissue, Inflammation, Chronic Active 1 (2%) Uterus (60) (60) (59) (60) Hemorrhage 1 (2%) Infiltration Cellular, Lymphocyte 1 (2%) Inflammation, Chronic 1 (2%) Endometrium, Hyperplasia, Cystic, Glandular 57 (95%) 58 (97%) 56 (95%) 53 (88%) Lymphatic, Ectasia 1 (2%) ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM Bone Marrow (60) (60) (60) (60) Myelofibrosis 7 (12%) 16 (27%) 4 (7%) 7 (12%) Myeloid Cell, Atrophy 1 (2%) Lymph Node (4) (8) (6) (9) Mediastinal, Hyperplasia, Lymphoid 1 (25%) 1 (17%) Lymph Node, Mandibular (57) (59) (59) (59) Hyperplasia, Lymphoid 1 (2%) 2 (3%) 1 (2%) Lymph Node, Mesenteric (54) (59) (56) (59) Hematopoietic Cell Proliferation 1 (2%) Hyperplasia, Lymphoid 1 (2%) 1 (2%) Spleen (60) (60) (60) (60) Hematopoietic Cell Proliferation 3 (5%) 9 (15%) 3 (5%) 6 (10%) Hyperplasia, Lymphoid 5 (8%) 5 (8%) Necrosis 1 (2%) Thymus (55) (57) (58) (58) Atrophy 19 (35%) 28 (49%) 28 (48%) 22 (38%) Cyst 1 (2%) Hyperplasia, Lymphoid 1 (2%) 2 (3%) ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 4 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE FEMALE 0 MG/KG 100 300 1000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ INTEGUMENTARY SYSTEM Mammary Gland (58) (57) (60) (57) Hyperplasia, Glandular 1 (2%) Skin (60) (60) (60) (60) Acanthosis 1 (2%) Inguinal, Inflammation, Chronic 1 (2%) Site of Application-No Mass, Acanthosis 3 (5%) 1 (2%) 5 (8%) Site of Application-No Mass, Inflammation, Chronic 2 (3%) 2 (3%) 8 (13%) ____________________________________________________________________________________________________________________________________ MUSCULOSKELETAL SYSTEM Bone (60) (60) (60) (60) Vertebra, Coccygeal, Fracture 1 (2%) ____________________________________________________________________________________________________________________________________ NERVOUS SYSTEM Brain (60) (60) (60) (60) Compression 3 (5%) 3 (5%) 1 (2%) 1 (2%) Hemorrhage 2 (3%) Medulla, Hemorrhage 1 (2%) Peripheral Nerve (2) (1) (1) Sciatic, Degeneration 1 (100%) Spinal Cord (2) (1) (1) Nerve, Degeneration 1 (50%) 1 (100%) 1 (100%) White Matter, Degeneration 1 (100%) ____________________________________________________________________________________________________________________________________ RESPIRATORY SYSTEM Lung (60) (60) (60) (59) Hemorrhage, Focal 1 (2%) Inflammation, Chronic Active 1 (2%) 1 (2%) Mineralization, Focal 1 (2%) Alveolar Epithelium, Hyperplasia 1 (2%) 1 (2%) Alveolar Epithelium, Hyperplasia, Macrophage 1 (2%) Pleura, Hyperplasia 1 (2%) ____________________________________________________________________________________________________________________________________ SPECIAL SENSES SYSTEM Ear (1) (1) (1) Internal Ear, Hyperplasia, Glandular 1 (100%) Harderian Gland (1) (2) (1) Acinus, Hyperplasia 1 (50%) a Number of animals examined microscopically at site and number of animals with lesion Page 5 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE FEMALE 0 MG/KG 100 300 1000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ URINARY SYSTEM Kidney (60) (60) (60) (60) Amyloid Deposition 1 (2%) Inflammation, Chronic Active 1 (2%) Nephropathy, Chronic 22 (37%) 30 (50%) 30 (50%) 25 (42%) Cortex, Cyst 1 (2%) Cortex, Infarct 3 (5%) 2 (3%) Pelvis, Inflammation, Acute 1 (2%) Renal Tubule, Hyperplasia, Cystic 1 (2%) Renal Tubule, Necrosis 1 (2%) Urinary Bladder (60) (60) (59) (60) Inflammation, Chronic Active 1 (2%) 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 6 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE MALE 0 MG/KG 200 630 2000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ DISPOSITION SUMMARY Animals Initially In Study 60 60 60 60 Scheduled Sacrifice 10 10 10 10 Early Deaths Moribund Sacrifice 2 5 3 6 Natural Death 2 5 8 3 Survivors Terminal Sacrifice 46 39 39 41 Natural Death 1 Animals Examined Microscopically 60 60 60 60 ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM Gallbladder (59) (58) (58) (59) Cyst 1 (2%) Intestine Small, Jejunum (60) (60) (60) (60) Peyer's Patch, Hyperplasia, Lymphoid 1 (2%) Liver (60) (60) (60) (60) Basophilic Focus 7 (12%) 3 (5%) 4 (7%) 3 (5%) Clear Cell Focus 13 (22%) 11 (18%) 7 (12%) 5 (8%) Congestion 1 (2%) Cyst 1 (2%) Cytoplasmic Alteration 10 (17%) 17 (28%) 10 (17%) 16 (27%) Eosinophilic Focus 10 (17%) 17 (28%) 11 (18%) 24 (40%) Fatty Change 1 (2%) Hematopoietic Cell Proliferation 1 (2%) 1 (2%) 1 (2%) Infiltration Cellular, Lymphocyte 1 (2%) Karyomegaly 13 (22%) 18 (30%) 10 (17%) 18 (30%) Mixed Cell Focus 2 (3%) 3 (5%) Necrosis 1 (2%) 2 (3%) Thrombosis 1 (2%) Bile Duct, Hyperplasia 2 (3%) 2 (3%) 1 (2%) Hepatocyte, Cytoplasmic Alteration 3 (5%) 1 (2%) 1 (2%) 2 (3%) Hepatocyte, Cytoplasmic Alteration, Focal 1 (2%) Hepatocyte, Necrosis 1 (2%) Hepatocyte, Vacuolization Cytoplasmic, Multifocal 4 (7%) 6 (10%) 3 (5%) 6 (10%) Kupffer Cell, Hyperplasia 1 (2%) Oval Cell, Hyperplasia 12 (20%) 15 (25%) 10 (17%) 19 (32%) Mesentery (3) (1) Fat, Inflammation, Chronic 2 (67%) Pancreas (60) (60) (60) (60) Infiltration Cellular, Histiocyte 1 (2%) Acinus, Atrophy 3 (5%) 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 7 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE MALE 0 MG/KG 200 630 2000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM - CONT Artery, Inflammation, Chronic 1 (2%) Duct, Cyst 1 (2%) Stomach, Forestomach (60) (59) (60) (60) Acanthosis 1 (2%) 1 (2%) 1 (2%) Ulcer 2 (3%) Stomach, Glandular (60) (60) (60) (60) Dysplasia 2 (3%) Hyperplasia 1 (2%) Pigmentation 1 (2%) ____________________________________________________________________________________________________________________________________ CARDIOVASCULAR SYSTEM Heart (60) (60) (60) (60) Degeneration, Chronic 1 (2%) 1 (2%) 1 (2%) Atrium, Thrombosis 1 (2%) Coronary Artery, Polyarteritis, Chronic 2 (3%) ____________________________________________________________________________________________________________________________________ ENDOCRINE SYSTEM Adrenal Cortex (60) (60) (60) (60) Angiectasis 1 (2%) Developmental Malformation 1 (2%) 1 (2%) Hyperplasia 1 (2%) 2 (3%) 1 (2%) 3 (5%) Hypertrophy 17 (28%) 14 (23%) 16 (27%) 7 (12%) Necrosis 1 (2%) 2 (3%) Thrombosis 1 (2%) Vacuolization Cytoplasmic 7 (12%) 1 (2%) 2 (3%) Capsule, Accessory Adrenal Cortical Nodule 1 (2%) 2 (3%) 1 (2%) Capsule, Cyst 1 (2%) Capsule, Hyperplasia 1 (2%) Capsule, Spindle Cell, Hyperplasia 10 (17%) 4 (7%) 7 (12%) 4 (7%) Adrenal Medulla (60) (60) (60) (60) Hyperplasia 2 (3%) 3 (5%) 1 (2%) Necrosis 1 (2%) Parathyroid Gland (55) (52) (56) (54) Cyst 1 (2%) 1 (2%) Pituitary Gland (58) (59) (56) (59) Pars Distalis, Cyst 2 (3%) 1 (2%) 1 (2%) 3 (5%) Pars Distalis, Hyperplasia 2 (3%) 1 (2%) 1 (2%) Thyroid Gland (60) (60) (60) (60) Infiltration Cellular, Lymphocyte 1 (2%) Polyarteritis, Chronic 1 (2%) Follicle, Cyst 1 (2%) Follicular Cell, Hyperplasia 14 (23%) 12 (20%) 10 (17%) 9 (15%) ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 8 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE MALE 0 MG/KG 200 630 2000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ GENERAL BODY SYSTEM None ____________________________________________________________________________________________________________________________________ GENITAL SYSTEM Epididymis (60) (60) (60) (60) Granuloma Sperm 1 (2%) 2 (3%) 1 (2%) 2 (3%) Artery, Inflammation, Chronic 1 (2%) Preputial Gland (60) (60) (60) (60) Inflammation, Chronic 2 (3%) 1 (2%) 2 (3%) Inflammation, Chronic Active 1 (2%) 2 (3%) Duct, Ectasia 36 (60%) 43 (72%) 31 (52%) 24 (40%) Prostate (60) (60) (60) (60) Infiltration Cellular, Histiocyte 1 (2%) Inflammation, Chronic 1 (2%) 1 (2%) Seminal Vesicle (50) (50) (50) (50) Inflammation, Chronic 1 (2%) 1 (2%) Artery, Inflammation, Chronic 1 (2%) Testes (60) (60) (60) (60) Congestion 1 (2%) Germinal Epithelium, Atrophy 1 (2%) 1 (2%) Germinal Epithelium, Mineralization 1 (2%) ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM Bone Marrow (60) (59) (58) (59) Myelofibrosis 1 (2%) 1 (2%) Lymph Node, Mandibular (57) (57) (57) (57) Hyperplasia, Lymphoid 1 (2%) Lymph Node, Mesenteric (56) (57) (53) (55) Fibrosis 1 (2%) Hematopoietic Cell Proliferation 1 (2%) 3 (5%) 1 (2%) 1 (2%) Spleen (60) (60) (60) (60) Congestion 1 (2%) Hematopoietic Cell Proliferation 4 (7%) 6 (10%) 4 (7%) 8 (13%) Thymus (53) (46) (57) (52) Atrophy 14 (26%) 25 (54%) 19 (33%) 16 (31%) Cyst 1 (2%) Infiltration Cellular, Histiocyte 1 (2%) ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 9 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE MALE 0 MG/KG 200 630 2000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ INTEGUMENTARY SYSTEM Skin (60) (60) (60) (60) Ulcer 2 (3%) Hair Follicle, Sebaceous Gland, Site of Application-No Mass, Atrophy 1 (2%) 15 (25%) Inguinal, Acanthosis 1 (2%) Inguinal, Inflammation, Chronic 2 (3%) Inguinal, Ulcer 1 (2%) Inguinal, Subcutaneous Tissue, Edema 1 (2%) Site of Application-No Mass, Acanthosis 2 (3%) 2 (3%) 7 (12%) 17 (28%) Site of Application-No Mass, Inflammation, Chronic 2 (3%) 9 (15%) 16 (27%) Site of Application-No Mass, Ulcer 1 (2%) 2 (3%) 2 (3%) ____________________________________________________________________________________________________________________________________ MUSCULOSKELETAL SYSTEM Bone (60) (59) (58) (59) Cranium, Hyperostosis 1 (2%) ____________________________________________________________________________________________________________________________________ NERVOUS SYSTEM Brain (60) (60) (60) (60) Pons, Necrosis, Chronic, Focal 1 (2%) Peripheral Nerve (1) (1) (1) Sciatic, Degeneration 1 (100%) 1 (100%) Spinal Cord (1) (1) (3) (1) Nerve, Degeneration 1 (33%) 1 (100%) White Matter, Degeneration 1 (100%) ____________________________________________________________________________________________________________________________________ RESPIRATORY SYSTEM Lung (60) (60) (60) (60) Inflammation, Chronic 1 (2%) 2 (3%) Alveolar Epithelium, Hyperplasia 3 (5%) 4 (7%) 2 (3%) 2 (3%) Alveolar Epithelium, Hyperplasia, Macrophage 1 (2%) 1 (2%) Alveolus, Hemorrhage, Multifocal 1 (2%) Mediastinum, Infiltration Cellular, Histiocyte 1 (2%) ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 10 NTP Experiment-Test: 05109-12 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC TRIETHANOLAMINE Date: 05/20/95 Route: DERMAL,SOLUTION Time: 00:11:45 ____________________________________________________________________________________________________________________________________ B6C3F1 MICE MALE 0 MG/KG 200 630 2000 MG/KG MG/KG MG/KG ____________________________________________________________________________________________________________________________________ SPECIAL SENSES SYSTEM Eye (3) (1) Cornea, Inflammation, Chronic 3 (100%) Cornea, Inflammation, Chronic, Proliferative 1 (100%) Harderian Gland (4) (5) (6) (1) Hyperplasia 1 (17%) ____________________________________________________________________________________________________________________________________ URINARY SYSTEM Kidney (60) (60) (60) (60) Hydronephrosis 2 (3%) 1 (2%) Metaplasia, Osseous 1 (2%) Mineralization 1 (2%) Nephropathy, Chronic 55 (92%) 54 (90%) 55 (92%) 56 (93%) Cortex, Cyst 4 (7%) 4 (7%) 2 (3%) a Number of animals examined microscopically at site and number of animals with lesion Page 11 ------------------------------------------------------------ ---------- END OF REPORT ---------- ------------------------------------------------------------