TDMS Study 05094-99 Pathology Tables
INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) BUTYL BENZYL PHTHALATE NTP Experiment-Test: 05094-99 Report: PEIRPT03 Study Type: CHRONIC Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 05094/02 -VS- 05094/03 COMPARISON Facility: SOUTHERN RESEARCH INSTITUTE Chemical CAS #: 85-68-7 Lock Date: 11/25/92 Cage Range: All Reasons For Removal: 25022 Accidently Killed 25004 Dead 25005 Interval Sacrifice 25003 Moribund 25019 Moribund Sacrifice 25020 Natural Death 25026 Other 25021 Terminal Sacrifice Removal Date Range: All Treatment Groups: Include 001 AD LIB CONTROL Include 002 AD LIB CONTROL Include 005 RTD CONTROL Include 006 RTD CONTROL a Number of animals examined microscopically at site and number of animals with lesion Page 1 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS FEMALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ DISPOSITION SUMMARY Animals Initially In Study 60 110 Scheduled Sacrifice 35 Early Deaths Moribund Sacrifice 23 2 Natural Death 2 Dead 4 Moribund 11 Survivors Terminal Sacrifice 25 Animals Examined Microscopically 50 52 ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM Intestine Large, Colon (50) (52) Parasite Metazoan 3 (6%) 6 (12%) Intestine Large, Rectum (50) (52) Parasite Metazoan 3 (6%) 4 (8%) Intestine Large, Cecum (50) (52) Edema 2 (4%) Parasite Metazoan 2 (4%) Intestine Small, Ileum (49) (52) Ulcer 1 (2%) Liver (50) (52) Angiectasis 1 (2%) Basophilic Focus 37 (74%) 41 (79%) Clear Cell Focus 3 (6%) 3 (6%) Developmental Malformation 1 (2%) 1 (2%) Eosinophilic Focus 19 (38%) 13 (25%) Granuloma 6 (12%) 8 (15%) Hematopoietic Cell Proliferation 1 (2%) Hepatodiaphragmatic Nodule 9 (18%) 3 (6%) Inflammation, Subacute 3 (6%) 3 (6%) Mixed Cell Focus 10 (20%) 5 (10%) Bile Duct, Hyperplasia 10 (20%) 5 (10%) Centrilobular, Necrosis 1 (2%) Hepatocyte, Vacuolization Cytoplasmic 7 (14%) Kupffer Cell, Hyperplasia 1 (2%) Kupffer Cell, Pigmentation 4 (8%) 1 (2%) Lobules, Necrosis 6 (12%) 6 (12%) Mesentery (10) (1) Accessory Spleen 1 (10%) 1 (100%) Fat, Necrosis 9 (90%) Pancreas (50) (49) a Number of animals examined microscopically at site and number of animals with lesion Page 2 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS FEMALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM - CONT Atrophy 18 (36%) 28 (57%) Acinus, Cytoplasmic Alteration 1 (2%) Acinus, Hyperplasia, Focal 1 (2%) Salivary Glands (49) (51) Atrophy 1 (2%) Hyperplasia 1 (2%) Stomach, Forestomach (50) (51) Edema 2 (4%) Ulcer 1 (2%) Mucosa, Hyperplasia 1 (2%) 1 (2%) Stomach, Glandular (50) (52) Erosion 1 (2%) 1 (2%) Inflammation, Chronic 1 (2%) Mineralization 1 (2%) Ulcer 3 (6%) Tongue (3) Epithelium, Hyperplasia 1 (33%) ____________________________________________________________________________________________________________________________________ CARDIOVASCULAR SYSTEM Heart (50) (52) Cardiomyopathy 16 (32%) 15 (29%) Thrombosis 1 (2%) ____________________________________________________________________________________________________________________________________ ENDOCRINE SYSTEM Adrenal Cortex (50) (52) Accessory Adrenal Cortical Nodule 5 (10%) 12 (23%) Angiectasis 22 (44%) 28 (54%) Degeneration, Fatty 10 (20%) 12 (23%) Hyperplasia, Focal 9 (18%) 4 (8%) Hypertrophy, Focal 9 (18%) 9 (17%) Adrenal Medulla (49) (51) Hyperplasia 1 (2%) 3 (6%) Pituitary Gland (49) (52) Pars Distalis, Angiectasis 7 (14%) 8 (15%) Pars Distalis, Cyst 24 (49%) 14 (27%) Pars Distalis, Hyperplasia, Focal 12 (24%) 11 (21%) Pars Intermedia, Angiectasis 1 (2%) Pars Intermedia, Cyst 4 (8%) Pars Intermedia, Hyperplasia 1 (2%) Thyroid Gland (49) (51) Ultimobranchial Cyst 2 (4%) C-Cell, Hyperplasia 6 (12%) 1 (2%) Follicle, Cyst 2 (4%) a Number of animals examined microscopically at site and number of animals with lesion Page 3 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS FEMALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ GENERAL BODY SYSTEM Tissue NOS (1) (1) Hemorrhage 1 (100%) ____________________________________________________________________________________________________________________________________ GENITAL SYSTEM Clitoral Gland (50) (52) Ectasia 12 (24%) 12 (23%) Hyperplasia 1 (2%) 1 (2%) Inflammation, Chronic 4 (8%) Inflammation, Suppurative 3 (6%) 5 (10%) Ovary (50) (52) Cyst 3 (6%) 4 (8%) Inflammation, Chronic 1 (2%) Uterus (50) (52) Hydrometra 2 (4%) 3 (6%) Hyperplasia, Cystic 4 (8%) 7 (13%) ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM Bone Marrow (50) (52) Hypercellularity 1 (2%) Myelofibrosis 4 (8%) 2 (4%) Lymph Node (12) (10) Mediastinal, Hemorrhage 1 (8%) 1 (10%) Mediastinal, Pigmentation 2 (17%) 3 (30%) Pancreatic, Pigmentation 1 (8%) 1 (10%) Renal, Hemorrhage 1 (10%) Renal, Pigmentation 1 (8%) Lymph Node, Mandibular (49) (51) Ectasia 1 (2%) 3 (6%) Hemorrhage 5 (10%) 5 (10%) Hyperplasia, Lymphoid 6 (12%) Pigmentation 12 (24%) 15 (29%) Lymph Node, Mesenteric (50) (52) Ectasia 1 (2%) Hemorrhage 3 (6%) 2 (4%) Hyperplasia, Lymphoid 1 (2%) 1 (2%) Spleen (50) (52) Fibrosis 1 (2%) 3 (6%) Hematopoietic Cell Proliferation 10 (20%) 13 (25%) Hemorrhage 2 (4%) Necrosis 1 (2%) Pigmentation, Hemosiderin 19 (38%) 21 (40%) a Number of animals examined microscopically at site and number of animals with lesion Page 4 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS FEMALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM - CONT Thymus (49) (52) Hemorrhage 1 (2%) ____________________________________________________________________________________________________________________________________ INTEGUMENTARY SYSTEM Mammary Gland (49) (52) Ectasia 12 (24%) 17 (33%) Galactocele 1 (2%) Hyperplasia 30 (61%) 18 (35%) Skin (50) (52) Acanthosis 1 (2%) 3 (6%) Cyst Epithelial Inclusion 1 (2%) Hyperkeratosis 3 (6%) 1 (2%) Inflammation, Chronic 1 (2%) Ulcer 2 (4%) 3 (6%) ____________________________________________________________________________________________________________________________________ MUSCULOSKELETAL SYSTEM Bone (50) (52) Cranium, Osteopetrosis 7 (14%) 12 (23%) Femur, Osteopetrosis 5 (10%) 7 (13%) Rib, Osteopetrosis 1 (2%) Skeletal Muscle (1) Hemorrhage 1 (100%) ____________________________________________________________________________________________________________________________________ NERVOUS SYSTEM Brain (50) (52) Compression 9 (18%) 5 (10%) Gliosis 1 (2%) Hydrocephalus 2 (4%) 1 (2%) ____________________________________________________________________________________________________________________________________ RESPIRATORY SYSTEM Lung (50) (52) Congestion 2 (4%) Edema 1 (2%) Infiltration Cellular, Histiocyte 21 (42%) 19 (37%) Inflammation, Subacute 1 (2%) 1 (2%) Alveolar Epithelium, Hyperplasia 2 (4%) 5 (10%) Nose (50) (52) Exudate 6 (12%) Foreign Body 5 (10%) 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 5 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS FEMALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ RESPIRATORY SYSTEM - CONT Fungus 3 (6%) Mucosa, Hyperplasia 3 (6%) 1 (2%) Mucosa, Metaplasia, Squamous 3 (6%) ____________________________________________________________________________________________________________________________________ SPECIAL SENSES SYSTEM Eye (2) (4) Atrophy 1 (50%) 1 (25%) Cataract 2 (50%) Hemorrhage 1 (50%) Retina, Degeneration 2 (50%) ____________________________________________________________________________________________________________________________________ URINARY SYSTEM Kidney (50) (52) Mineralization 43 (86%) 47 (90%) Nephropathy 34 (68%) 41 (79%) Renal Tubule, Cytoplasmic Alteration 1 (2%) Renal Tubule, Dilatation 1 (2%) Renal Tubule, Necrosis 1 (2%) Renal Tubule, Pigmentation 49 (98%) 50 (96%) Transitional Epithelium, Hyperplasia 1 (2%) Urinary Bladder (50) (52) Edema 1 (2%) Hyperplasia 1 (2%) Mucosa, Hyperplasia 2 (4%) Transitional Epithelium, Hyperplasia 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 6 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ DISPOSITION SUMMARY Animals Initially In Study 60 110 Scheduled Sacrifice 34 Early Deaths Moribund Sacrifice 19 Natural Death 3 Moribund 14 Dead 1 Survivors Terminal Sacrifice 28 Accidently Killed 1 Animals Examined Microscopically 50 50 ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM Intestine Large, Colon (44) (49) Dilatation 1 (2%) Parasite Metazoan 5 (11%) 4 (8%) Intestine Large, Rectum (49) (50) Parasite Metazoan 10 (20%) 5 (10%) Intestine Large, Cecum (47) (49) Edema 3 (6%) 1 (2%) Parasite Metazoan 1 (2%) Ulcer 1 (2%) 1 (2%) Liver (50) (50) Angiectasis 1 (2%) Basophilic Focus 22 (44%) 16 (32%) Clear Cell Focus 15 (30%) 1 (2%) Degeneration, Cystic 7 (14%) Developmental Malformation 2 (4%) Eosinophilic Focus 3 (6%) 6 (12%) Granuloma 1 (2%) Hematopoietic Cell Proliferation 2 (4%) Hepatodiaphragmatic Nodule 1 (2%) 2 (4%) Inflammation, Subacute 2 (4%) Mixed Cell Focus 6 (12%) 1 (2%) Bile Duct, Hyperplasia 39 (78%) 32 (64%) Centrilobular, Necrosis 1 (2%) Hepatocyte, Vacuolization Cytoplasmic 6 (12%) 4 (8%) Kupffer Cell, Hyperplasia 1 (2%) Kupffer Cell, Pigmentation 1 (2%) 3 (6%) Lobules, Necrosis 2 (4%) 1 (2%) Mesentery (7) (7) Accessory Spleen 2 (29%) a Number of animals examined microscopically at site and number of animals with lesion Page 7 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ ALIMENTARY SYSTEM - CONT Angiectasis 1 (14%) Fat, Necrosis 5 (71%) 5 (71%) Pancreas (50) (50) Atrophy 29 (58%) 36 (72%) Acinus, Cytoplasmic Alteration 1 (2%) 2 (4%) Acinus, Hyperplasia, Focal 4 (8%) Stomach, Forestomach (50) (50) Edema 1 (2%) 1 (2%) Ulcer 2 (4%) Mucosa, Hyperplasia 2 (4%) 1 (2%) Stomach, Glandular (50) (50) Edema 2 (4%) Erosion 2 (4%) 2 (4%) Ulcer 2 (4%) 1 (2%) ____________________________________________________________________________________________________________________________________ CARDIOVASCULAR SYSTEM Blood Vessel (50) (50) Hypertrophy 2 (4%) Inflammation, Subacute 2 (4%) Heart (50) (50) Cardiomyopathy 32 (64%) 25 (50%) Inflammation, Chronic 1 (2%) Thrombosis 2 (4%) 1 (2%) ____________________________________________________________________________________________________________________________________ ENDOCRINE SYSTEM Adrenal Cortex (50) (50) Accessory Adrenal Cortical Nodule 11 (22%) 18 (36%) Angiectasis 26 (52%) Degeneration, Fatty 3 (6%) 4 (8%) Hematopoietic Cell Proliferation 1 (2%) Hemorrhage 1 (2%) 1 (2%) Hyperplasia, Focal 7 (14%) 9 (18%) Hypertrophy, Focal 2 (4%) 3 (6%) Thrombosis 1 (2%) Vacuolization Cytoplasmic 1 (2%) Adrenal Medulla (50) (50) Hyperplasia 6 (12%) 9 (18%) Islets, Pancreatic (50) (50) Hyperplasia 3 (6%) 1 (2%) Pituitary Gland (50) (46) Pars Distalis, Angiectasis 3 (6%) 2 (4%) Pars Distalis, Cyst 3 (6%) 6 (13%) Pars Distalis, Hyperplasia 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 8 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ ENDOCRINE SYSTEM - CONT Pars Distalis, Hyperplasia, Focal 7 (14%) 13 (28%) Pars Intermedia, Angiectasis 3 (6%) Pars Intermedia, Cyst 1 (2%) 1 (2%) Thyroid Gland (50) (50) Ultimobranchial Cyst 2 (4%) C-Cell, Hyperplasia 4 (8%) 5 (10%) Follicle, Cyst 2 (4%) 3 (6%) ____________________________________________________________________________________________________________________________________ GENERAL BODY SYSTEM None ____________________________________________________________________________________________________________________________________ GENITAL SYSTEM Epididymis (50) (50) Atypia Cellular 28 (56%) 39 (78%) Hypospermia 34 (68%) 38 (76%) Preputial Gland (50) (50) Ectasia 11 (22%) 16 (32%) Hyperplasia 1 (2%) 1 (2%) Inflammation, Chronic 25 (50%) 26 (52%) Inflammation, Suppurative 9 (18%) 9 (18%) Prostate (50) (49) Corpora Amylacea 17 (34%) 22 (45%) Inflammation, Suppurative 29 (58%) 22 (45%) Epithelium, Hyperplasia 4 (8%) 5 (10%) Seminal Vesicle (50) (50) Dilatation 4 (8%) 1 (2%) Testes (50) (50) Interstitial Cell, Hyperplasia 4 (8%) 4 (8%) Seminiferous Tubule, Atrophy 2 (4%) 4 (8%) ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM Bone Marrow (50) (50) Hypercellularity 1 (2%) 2 (4%) Myelofibrosis 2 (4%) 5 (10%) Lymph Node (23) (12) Iliac, Hemorrhage 1 (4%) Iliac, Hyperplasia, Lymphoid 1 (4%) Iliac, Pigmentation 1 (4%) Mediastinal, Hemorrhage 5 (22%) 1 (8%) Mediastinal, Pigmentation 5 (22%) 7 (58%) Pancreatic, Pigmentation 4 (33%) a Number of animals examined microscopically at site and number of animals with lesion Page 9 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ HEMATOPOIETIC SYSTEM - CONT Renal, Hyperplasia, Lymphoid 1 (4%) Renal, Pigmentation 2 (9%) 1 (8%) Lymph Node, Mandibular (49) (48) Congestion 1 (2%) Ectasia 6 (12%) 5 (10%) Hemorrhage 4 (8%) 5 (10%) Hyperplasia, Lymphoid 3 (6%) 2 (4%) Pigmentation 2 (4%) 10 (21%) Lymph Node, Mesenteric (50) (50) Ectasia 6 (12%) 2 (4%) Hemorrhage 1 (2%) 2 (4%) Hyperplasia, Lymphoid 2 (4%) 1 (2%) Spleen (50) (50) Developmental Malformation 1 (2%) Fibrosis 5 (10%) 7 (14%) Hematopoietic Cell Proliferation 2 (4%) 5 (10%) Metaplasia, Osseous 1 (2%) Necrosis 1 (2%) Pigmentation, Hemosiderin 14 (28%) 6 (12%) Lymphoid Follicle, Hyperplasia 1 (2%) Thymus (49) (46) Hemorrhage 1 (2%) ____________________________________________________________________________________________________________________________________ INTEGUMENTARY SYSTEM Mammary Gland (45) (49) Hyperplasia 10 (22%) 7 (14%) Skin (50) (49) Acanthosis 2 (4%) Hemorrhage 1 (2%) Hyperkeratosis 2 (4%) Inflammation, Chronic, Focal 1 (2%) Metaplasia, Osseous 1 (2%) Ulcer 1 (2%) ____________________________________________________________________________________________________________________________________ MUSCULOSKELETAL SYSTEM Bone (50) (50) Cranium, Osteopetrosis 1 (2%) 2 (4%) Femur, Osteopetrosis 2 (4%) ____________________________________________________________________________________________________________________________________ a Number of animals examined microscopically at site and number of animals with lesion Page 10 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ NERVOUS SYSTEM Brain (50) (50) Compression 4 (8%) 2 (4%) Hydrocephalus 2 (4%) 1 (2%) Mineralization 1 (2%) ____________________________________________________________________________________________________________________________________ RESPIRATORY SYSTEM Lung (50) (50) Congestion 1 (2%) Edema 1 (2%) Infiltration Cellular, Histiocyte 13 (26%) 4 (8%) Inflammation, Subacute 1 (2%) 1 (2%) Inflammation, Suppurative 1 (2%) Metaplasia, Osseous 1 (2%) Alveolar Epithelium, Hyperplasia 7 (14%) 5 (10%) Nose (50) (50) Exudate 17 (34%) 5 (10%) Foreign Body 8 (16%) Fungus 12 (24%) 4 (8%) Mucosa, Hyperplasia 11 (22%) 3 (6%) Mucosa, Metaplasia, Squamous 9 (18%) 3 (6%) ____________________________________________________________________________________________________________________________________ SPECIAL SENSES SYSTEM Eye (1) Atrophy 1 (100%) ____________________________________________________________________________________________________________________________________ URINARY SYSTEM Kidney (50) (50) Calculus Micro Observation Only 1 (2%) Mineralization 5 (10%) Nephropathy 48 (96%) 43 (86%) Renal Tubule, Dilatation 2 (4%) Renal Tubule, Necrosis 1 (2%) Renal Tubule, Pigmentation 49 (98%) 47 (94%) Transitional Epithelium, Hyperplasia 6 (12%) 1 (2%) Urinary Bladder (50) (50) a Number of animals examined microscopically at site and number of animals with lesion Page 11 NTP Experiment-Test: 05094-99 INCIDENCE RATES OF NONNEOPLASTIC LESIONS BY ANATOMIC SITE (a) Report: PEIRPT03 Study Type: CHRONIC BUTYL BENZYL PHTHALATE Date: 05/10/95 Route: DOSED FEED Time: 17:12:30 ____________________________________________________________________________________________________________________________________ FISCHER 344 RATS MALE AD LIB RTD CONTROL CONTROL ____________________________________________________________________________________________________________________________________ URINARY SYSTEM - CONT Transitional Epithelium, Hyperplasia 1 (2%) a Number of animals examined microscopically at site and number of animals with lesion Page 12 ------------------------------------------------------------ ---------- END OF REPORT ---------- ------------------------------------------------------------