javicorvi/pretoxtm-dataset · Datasets at Hugging Face

label stringclasses 2 values	text stringlengths 1 1.95k	tokens sequencelengths 1 371	ner_tags sequencelengths 1 371	ner_tag_codes sequencelengths 1 371
PRETOX_REL	The relevance of the decreased liver weight in high dose males at the end of the treatment period is unclear .	[ "The", "relevance", "of", "the", "decreased", "liver", "weight", "in", "high", "dose", "males", "at", "the", "end", "of", "the", "treatment", "period", "is", "unclear", "." ]	[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 1, 10, 2, 0, 15, 16, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	There was bright yellow urine in the bladder .	[ "There", "was", "bright", "yellow", "urine", "in", "the", "bladder", "." ]	[ "O", "O", "B-FINDING", "I-FINDING", "B-SPECIMEN", "O", "O", "B-SPECIMEN", "O" ]	[ 0, 0, 8, 9, 10, 0, 0, 10, 0 ]
NO_PRETOX_REL	Dogs were constituted within 4 different groups receiving oral doses of placebo ( control group , group 1 ) , 5 ( group 2 ) , 15 ( group 3 ) and 60 or 70 ( group 4 ) mg / kg / day for 52 weeks .	[ "Dogs", "were", "constituted", "within", "4", "different", "groups", "receiving", "oral", "doses", "of", "placebo", "(", "control", "group", ",", "group", "1", ")", ",", "5", "(", "group", "2", ")", ",", "15", "(", "group", "3", ")", "and", "60", "or", "70", "(", "group", "4", ")", "mg", "/", "kg", "/", "day", "for", "52", "weeks", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 12, 13, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Tissues with high mitotic activity are a known target for compounds of this class .	[ "Tissues", "with", "high", "mitotic", "activity", "are", "a", "known", "target", "for", "compounds", "of", "this", "class", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The mean values of these groups on day 5 were 2 - 4 % lower than those at the beginning of the treatment .	[ "The", "mean", "values", "of", "these", "groups", "on", "day", "5", "were", "2", "-", "4", "%", "lower", "than", "those", "at", "the", "beginning", "of", "the", "treatment", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	A reversal of these changes was observed during the recovery period .	[ "A", "reversal", "of", "these", "changes", "was", "observed", "during", "the", "recovery", "period", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The purpose of this nonclinical laboratory study was to establish the toxicologic effects of COMPOUND_XXX , a potent inhibitor of the Bcr - Abl tyrosine kinases , foreseen primarily in the treatment of chronic myeloid leukemia , when administered to dogs for 4 weeks .	[ "The", "purpose", "of", "this", "nonclinical", "laboratory", "study", "was", "to", "establish", "the", "toxicologic", "effects", "of", "COMPOUND_XXX", ",", "a", "potent", "inhibitor", "of", "the", "Bcr", "-", "Abl", "tyrosine", "kinases", ",", "foreseen", "primarily", "in", "the", "treatment", "of", "chronic", "myeloid", "leukemia", ",", "when", "administered", "to", "dogs", "for", "4", "weeks", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The decrease in erythron mass and altered erythroid indices were attributed to a recrudescence of the Plasmodium sp causing increased red cell parasitism and destruction .	[ "The", "decrease", "in", "erythron", "mass", "and", "altered", "erythroid", "indices", "were", "attributed", "to", "a", "recrudescence", "of", "the", "Plasmodium", "sp", "causing", "increased", "red", "cell", "parasitism", "and", "destruction", "." ]	[ "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-FINDING", "O", "B-FINDING", "O" ]	[ 0, 1, 0, 2, 6, 0, 8, 9, 9, 0, 0, 0, 0, 8, 9, 9, 9, 9, 0, 1, 0, 10, 8, 0, 8, 0 ]
NO_PRETOX_REL	Two patches were applied at each dosing in groups 1 , 3 and 4 , and one patch was applied in group 2 .	[ "Two", "patches", "were", "applied", "at", "each", "dosing", "in", "groups", "1", ",", "3", "and", "4", ",", "and", "one", "patch", "was", "applied", "in", "group", "2", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
PRETOX_REL	Other signs observed only in the Mid-High and High dose groups were excessive grooming , decreased locomotor activity , ataxia and flattened body position .	[ "Other", "signs", "observed", "only", "in", "the", "Mid-High", "and", "High", "dose", "groups", "were", "excessive", "grooming", ",", "decreased", "locomotor", "activity", ",", "ataxia", "and", "flattened", "body", "position", "." ]	[ "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-FINDING", "I-FINDING", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 0, 0, 0, 0, 0, 0, 12, 13, 13, 13, 13, 0, 8, 9, 0, 1, 2, 6, 0, 8, 0, 8, 9, 9, 0 ]
NO_PRETOX_REL	In hematology including coagulation , clinical chemistry and urinalysis no treatment - related alterations were seen .	[ "In", "hematology", "including", "coagulation", ",", "clinical", "chemistry", "and", "urinalysis", "no", "treatment", "-", "related", "alterations", "were", "seen", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In addition , hypertrophy of acinar cells in salivary and lacrimal glands were observed from the low dose upwards .	[ "In", "addition", ",", "hypertrophy", "of", "acinar", "cells", "in", "salivary", "and", "lacrimal", "glands", "were", "observed", "from", "the", "low", "dose", "upwards", "." ]	[ "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O" ]	[ 0, 0, 0, 8, 0, 0, 0, 0, 10, 0, 10, 11, 0, 0, 0, 0, 15, 16, 0, 0 ]
NO_PRETOX_REL	Blood samples for toxicokinetics were taken on the first day of dosing and in week I3 and 26 of dosing .	[ "Blood", "samples", "for", "toxicokinetics", "were", "taken", "on", "the", "first", "day", "of", "dosing", "and", "in", "week", "I3", "and", "26", "of", "dosing", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Urinalysis revealed a decrease in urinary volume accompanied by an increase in the urine specific gravity and urine creatinine concentrations , and a mild increase in urinary protein , urobilinogen and total leukocytes .	[ "Urinalysis", "revealed", "a", "decrease", "in", "urinary", "volume", "accompanied", "by", "an", "increase", "in", "the", "urine", "specific", "gravity", "and", "urine", "creatinine", "concentrations", ",", "and", "a", "mild", "increase", "in", "urinary", "protein", ",", "urobilinogen", "and", "total", "leukocytes", "." ]	[ "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]	[ 0, 0, 0, 1, 0, 2, 6, 0, 0, 0, 1, 0, 0, 2, 6, 6, 0, 2, 6, 0, 0, 0, 0, 0, 1, 0, 2, 6, 0, 2, 0, 2, 6, 0 ]
NO_PRETOX_REL	These findings were consistent with those from earlier toxicity studies with COMPOUND_XXX , occurred with similar incidence and severity between the two synthetic lots , and were associated with a similar toxicokinetic profile .	[ "These", "findings", "were", "consistent", "with", "those", "from", "earlier", "toxicity", "studies", "with", "COMPOUND_XXX", ",", "occurred", "with", "similar", "incidence", "and", "severity", "between", "the", "two", "synthetic", "lots", ",", "and", "were", "associated", "with", "a", "similar", "toxicokinetic", "profile", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	COMPOUND_XXX and COMPOUND_ZZZ were detected in all treated animals indicating that the dogs were exposed to the compounds ( parent and its metabolite ) suggesting drug absorption at all dose levels .	[ "COMPOUND_XXX", "and", "COMPOUND_ZZZ", "were", "detected", "in", "all", "treated", "animals", "indicating", "that", "the", "dogs", "were", "exposed", "to", "the", "compounds", "(", "parent", "and", "its", "metabolite", ")", "suggesting", "drug", "absorption", "at", "all", "dose", "levels", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	In addition , a secondary concentration peak , indicating enterohepatic recirculation of the drug , was observed in several animals .	[ "In", "addition", ",", "a", "secondary", "concentration", "peak", ",", "indicating", "enterohepatic", "recirculation", "of", "the", "drug", ",", "was", "observed", "in", "several", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Mean COMPOUND_XXX concentrations in the duodenal mucosa of 2560 and 25400 ng / g tissue and in the duodenal content of 6430 and 62400 ng / g at 20 and 180 mg / kg , respectively , appeared to increase roughly proportionally with the dose , but individual values showed a high inter-animal variability .	[ "Mean", "COMPOUND_XXX", "concentrations", "in", "the", "duodenal", "mucosa", "of", "2560", "and", "25400", "ng", "/", "g", "tissue", "and", "in", "the", "duodenal", "content", "of", "6430", "and", "62400", "ng", "/", "g", "at", "20", "and", "180", "mg", "/", "kg", ",", "respectively", ",", "appeared", "to", "increase", "roughly", "proportionally", "with", "the", "dose", ",", "but", "individual", "values", "showed", "a", "high", "inter-animal", "variability", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Post-mortem examinations revealed neither systemic nor local effects attributable to the dermal treatment with the test item or its placebo formulation .	[ "Post-mortem", "examinations", "revealed", "neither", "systemic", "nor", "local", "effects", "attributable", "to", "the", "dermal", "treatment", "with", "the", "test", "item", "or", "its", "placebo", "formulation", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	XXXXX ) , of identical design , that was performed using two dosage levels of D6 ( also known as COMPOUND_XXX ) , a minor metabolite of COMPOUND_XXX in rats .	[ "XXXXX", ")", ",", "of", "identical", "design", ",", "that", "was", "performed", "using", "two", "dosage", "levels", "of", "D6", "(", "also", "known", "as", "COMPOUND_XXX", ")", ",", "a", "minor", "metabolite", "of", "COMPOUND_XXX", "in", "rats", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The NOAEL ( No Observed Adverse Effect Level ) is considered to be 0.01 mg / kg / day .	[ "The", "NOAEL", "(", "No", "Observed", "Adverse", "Effect", "Level", ")", "is", "considered", "to", "be", "0.01", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
PRETOX_REL	In females , the mean total protein concentration was lower ( - 9 % ) and a tendency towards higher values was noted in alkaline phosphatase activities ( +32 % ) .	[ "In", "females", ",", "the", "mean", "total", "protein", "concentration", "was", "lower", "(", "-", "9", "%", ")", "and", "a", "tendency", "towards", "higher", "values", "was", "noted", "in", "alkaline", "phosphatase", "activities", "(", "+32", "%", ")", "." ]	[ "O", "B-SEX", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "O" ]	[ 0, 5, 0, 0, 2, 6, 6, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 2, 6, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No changes were seen in body weight , or food and water consumption of female animals at 25 mg / kg .	[ "No", "changes", "were", "seen", "in", "body", "weight", ",", "or", "food", "and", "water", "consumption", "of", "female", "animals", "at", "25", "mg", "/", "kg", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0 ]
NO_PRETOX_REL	Protocol - specified organs were weighed and tissues were collected , processed and microscopically examined on all animals .	[ "Protocol", "-", "specified", "organs", "were", "weighed", "and", "tissues", "were", "collected", ",", "processed", "and", "microscopically", "examined", "on", "all", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Test article - related microscopic changes in the spleen were decreased cellularity , lymphocytic , in all males and 9/10 females at 0.9 mglkg with decreased cellularity , red pulp in 2110 males and increased extramedullary hematopoiesis in all females at 0.9 mg / kg and 9/10 females at both 0.05 and 0.3 mglkg .	[ "Test", "article", "-", "related", "microscopic", "changes", "in", "the", "spleen", "were", "decreased", "cellularity", ",", "lymphocytic", ",", "in", "all", "males", "and", "9/10", "females", "at", "0.9", "mglkg", "with", "decreased", "cellularity", ",", "red", "pulp", "in", "2110", "males", "and", "increased", "extramedullary", "hematopoiesis", "in", "all", "females", "at", "0.9", "mg", "/", "kg", "and", "9/10", "females", "at", "both", "0.05", "and", "0.3", "mglkg", "." ]	[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 8, 9, 0, 0, 10, 0, 1, 2, 0, 2, 0, 0, 0, 5, 0, 0, 5, 0, 3, 4, 0, 1, 2, 0, 8, 9, 0, 0, 5, 0, 8, 9, 9, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 5, 0, 0, 3, 4, 4, 4, 0 ]
PRETOX_REL	Changes in cholesterol , triglycerides and alkaline phosphatase were additional evidences of liver metabolism dysfunction with both test - items .	[ "Changes", "in", "cholesterol", ",", "triglycerides", "and", "alkaline", "phosphatase", "were", "additional", "evidences", "of", "liver", "metabolism", "dysfunction", "with", "both", "test", "-", "items", "." ]	[ "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-SPECIMEN", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O" ]	[ 1, 0, 2, 0, 2, 0, 2, 6, 0, 0, 0, 0, 10, 8, 9, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	+ EN ATTENTE BIOMARQUEURS , with corresponding Cmax and AUC values in male / female rats of 1170/2140 ng / mL and 14600 / 18700 ng.h / mL , respectively .	[ "+", "EN", "ATTENTE", "BIOMARQUEURS", ",", "with", "corresponding", "Cmax", "and", "AUC", "values", "in", "male", "/", "female", "rats", "of", "1170/2140", "ng", "/", "mL", "and", "14600", "/", "18700", "ng.h", "/", "mL", ",", "respectively", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Plasma levels were above the limit of quantification during the complete dosing interval .	[ "Plasma", "levels", "were", "above", "the", "limit", "of", "quantification", "during", "the", "complete", "dosing", "interval", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The following investigations were performed : mortality , clinical signs , body weight , food consumption , plasma concentrations of COMPOUND_XXX ( before necropsy ) , macroscopic examination and histopathology of selected organs ( jejunum , ileum , colon , liver , pancreas and spleen ) .	[ "The", "following", "investigations", "were", "performed", ":", "mortality", ",", "clinical", "signs", ",", "body", "weight", ",", "food", "consumption", ",", "plasma", "concentrations", "of", "COMPOUND_XXX", "(", "before", "necropsy", ")", ",", "macroscopic", "examination", "and", "histopathology", "of", "selected", "organs", "(", "jejunum", ",", "ileum", ",", "colon", ",", "liver", ",", "pancreas", "and", "spleen", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No treatment - related effects were observed on food consumption .	[ "No", "treatment", "-", "related", "effects", "were", "observed", "on", "food", "consumption", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The one high - dose male recovery animal ( the other recovery animal died during the study ) showed increased liver weight and altered liver histology that did not show evidence of recovery .	[ "The", "one", "high", "-", "dose", "male", "recovery", "animal", "(", "the", "other", "recovery", "animal", "died", "during", "the", "study", ")", "showed", "increased", "liver", "weight", "and", "altered", "liver", "histology", "that", "did", "not", "show", "evidence", "of", "recovery", "." ]	[ "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 15, 16, 16, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 10, 2, 0, 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The severe skin erythema appeared from approximately day 9 .	[ "The", "severe", "skin", "erythema", "appeared", "from", "approximately", "day", "9", "." ]	[ "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 8, 9, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In another female of this dose group mild acute multifocal bilateral hemorrhages were seen in the corpora lutea .	[ "In", "another", "female", "of", "this", "dose", "group", "mild", "acute", "multifocal", "bilateral", "hemorrhages", "were", "seen", "in", "the", "corpora", "lutea", "." ]	[ "O", "O", "B-SEX", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 5, 0, 0, 12, 13, 0, 0, 8, 9, 9, 0, 0, 0, 0, 10, 11, 0 ]
NO_PRETOX_REL	Approximately proportional increases in COMPOUND_XXX plasma concentrations were seen with increased dose .	[ "Approximately", "proportional", "increases", "in", "COMPOUND_XXX", "plasma", "concentrations", "were", "seen", "with", "increased", "dose", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	At necropsy light yellow discoloration of the xiphoid cartilage was observed grossly in both male and female rats , and bright yellow urine was present in the bladder .	[ "At", "necropsy", "light", "yellow", "discoloration", "of", "the", "xiphoid", "cartilage", "was", "observed", "grossly", "in", "both", "male", "and", "female", "rats", ",", "and", "bright", "yellow", "urine", "was", "present", "in", "the", "bladder", "." ]	[ "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O", "O", "B-FINDING", "I-FINDING", "B-SPECIMEN", "O", "O", "O", "O", "B-SPECIMEN", "O" ]	[ 0, 0, 8, 9, 9, 0, 0, 10, 11, 0, 0, 0, 0, 0, 5, 7, 7, 0, 0, 0, 8, 9, 10, 0, 0, 0, 0, 10, 0 ]
PRETOX_REL	Serum creatinine and BUN were slightly increased in female rats .	[ "Serum", "creatinine", "and", "BUN", "were", "slightly", "increased", "in", "female", "rats", "." ]	[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SEX", "O", "O" ]	[ 2, 6, 0, 2, 0, 0, 1, 0, 5, 0, 0 ]
PRETOX_REL	Clinical findings prior to death were apathy , emaciation , prone , lateral or supine position , disturbances in gait and vomiting	[ "Clinical", "findings", "prior", "to", "death", "were", "apathy", ",", "emaciation", ",", "prone", ",", "lateral", "or", "supine", "position", ",", "disturbances", "in", "gait", "and", "vomiting" ]	[ "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING" ]	[ 0, 0, 0, 0, 0, 0, 8, 0, 8, 0, 8, 9, 9, 9, 9, 9, 0, 8, 9, 9, 0, 8 ]
NO_PRETOX_REL	Control animals similarly received the vehicle for the test item ( Millipore water ) at a dosage volume of 5 mL / kg .	[ "Control", "animals", "similarly", "received", "the", "vehicle", "for", "the", "test", "item", "(", "Millipore", "water", ")", "at", "a", "dosage", "volume", "of", "5", "mL", "/", "kg", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Additionally , a slight to moderate increase in severity of the hyaline droplet content in the proximal convoluted tubules of 4/5 males was observed .	[ "Additionally", ",", "a", "slight", "to", "moderate", "increase", "in", "severity", "of", "the", "hyaline", "droplet", "content", "in", "the", "proximal", "convoluted", "tubules", "of", "4/5", "males", "was", "observed", "." ]	[ "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "B-SEX", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 8, 9, 9, 0, 0, 10, 11, 11, 0, 0, 5, 0, 0, 0 ]
NO_PRETOX_REL	Formulation 10 % ( variant 11 ) and On days 1 , 3 and 5 , test items were applicated for 47 hours on the areas of the left flank .	[ "Formulation", "10", "%", "(", "variant", "11", ")", "and", "On", "days", "1", ",", "3", "and", "5", ",", "test", "items", "were", "applicated", "for", "47", "hours", "on", "the", "areas", "of", "the", "left", "flank", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Dose levels up to and including 1000 mg / kg / day were well tolerated .	[ "Dose", "levels", "up", "to", "and", "including", "1000", "mg", "/", "kg", "/", "day", "were", "well", "tolerated", "." ]	[ "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0 ]
PRETOX_REL	Group mean body weight loss was frequently seen in both groups of treated males and for females during treatment at 75 mg / kg / day .	[ "Group", "mean", "body", "weight", "loss", "was", "frequently", "seen", "in", "both", "groups", "of", "treated", "males", "and", "for", "females", "during", "treatment", "at", "75", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-SEX", "O", "O", "B-SEX", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 2, 6, 1, 0, 0, 0, 0, 12, 13, 0, 0, 5, 0, 0, 5, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	The checks on the body temperatures yielded no changes up to and including group III ( for individual and mean values see appendix of the report ) .	[ "The", "checks", "on", "the", "body", "temperatures", "yielded", "no", "changes", "up", "to", "and", "including", "group", "III", "(", "for", "individual", "and", "mean", "values", "see", "appendix", "of", "the", "report", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The degenerative testicular changes observed microscopically at all dose levels were considered to be related to the pharmacologic effect of COMPOUND_XXX .	[ "The", "degenerative", "testicular", "changes", "observed", "microscopically", "at", "all", "dose", "levels", "were", "considered", "to", "be", "related", "to", "the", "pharmacologic", "effect", "of", "COMPOUND_XXX", "." ]	[ "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 8, 9, 9, 0, 0, 0, 3, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Females tended to be more affected .	[ "Females", "tended", "to", "be", "more", "affected", "." ]	[ "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Ophthalmoscopy Ophthalmoskopy showed a light center of the yellow spot in one animal from group 3 ( 40 umol / kg bw . )	[ "Ophthalmoscopy", "Ophthalmoskopy", "showed", "a", "light", "center", "of", "the", "yellow", "spot", "in", "one", "animal", "from", "group", "3", "(", "40", "umol", "/", "kg", "bw", ".", ")" ]	[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]	[ 0, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0, 0, 0, 0, 12, 13, 0, 3, 4, 4, 4, 4, 0, 0 ]
NO_PRETOX_REL	d. Ophthalmoscopic findings The individual data for the ophthalmoscopic investigations can be found in the appendix of the report .	[ "d.", "Ophthalmoscopic", "findings", "The", "individual", "data", "for", "the", "ophthalmoscopic", "investigations", "can", "be", "found", "in", "the", "appendix", "of", "the", "report", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Hematology No compound - related effect was observed .	[ "Hematology", "No", "compound", "-", "related", "effect", "was", "observed", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	In conclusion , the oral ( gavage ) administration of COMPOUND_XXX to male rats at dosages of 40 and 80 mg / kg over up to 4 weeks was well tolerated without mortality or clinical signs of toxicity .	[ "In", "conclusion", ",", "the", "oral", "(", "gavage", ")", "administration", "of", "COMPOUND_XXX", "to", "male", "rats", "at", "dosages", "of", "40", "and", "80", "mg", "/", "kg", "over", "up", "to", "4", "weeks", "was", "well", "tolerated", "without", "mortality", "or", "clinical", "signs", "of", "toxicity", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Gravimetric organ findings The absolute and relative organ weights are listed in the appendix of the report in the form of individual values , mean values per group and per sex with their standard deviations , and mean values separately for each sex and for the two sexes together .	[ "Gravimetric", "organ", "findings", "The", "absolute", "and", "relative", "organ", "weights", "are", "listed", "in", "the", "appendix", "of", "the", "report", "in", "the", "form", "of", "individual", "values", ",", "mean", "values", "per", "group", "and", "per", "sex", "with", "their", "standard", "deviations", ",", "and", "mean", "values", "separately", "for", "each", "sex", "and", "for", "the", "two", "sexes", "together", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	In - life and terminal data collection during the treatment and recovery periods included clinical observations , body weight , food consumption , ophthalmic and neurologic examinations , hematology , clinical chemistry , urinalysis and a complete necropsy of all toxicity animals that died during study .	[ "In", "-", "life", "and", "terminal", "data", "collection", "during", "the", "treatment", "and", "recovery", "periods", "included", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "ophthalmic", "and", "neurologic", "examinations", ",", "hematology", ",", "clinical", "chemistry", ",", "urinalysis", "and", "a", "complete", "necropsy", "of", "all", "toxicity", "animals", "that", "died", "during", "study", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	As the table shows , the nutritional state showed no relevant changes up to and including group III .	[ "As", "the", "table", "shows", ",", "the", "nutritional", "state", "showed", "no", "relevant", "changes", "up", "to", "and", "including", "group", "III", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL	The animal No 7088 ( F g r .	[ "The", "animal", "No", "7088", "(", "F", "g", "r", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	of COMPOUND_XXX but remained within the physiological range in all treatment groups .	[ "of", "COMPOUND_XXX", "but", "remained", "within", "the", "physiological", "range", "in", "all", "treatment", "groups", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL	In addition , one control group ( 4 female monkeys ) received the vehicle at an application volume of 2.5 mL / kg body weight in the same manner and another control group ( 4 female monkeys ) received 0.9 % ( w / v ) sodium chloride solution at an application volume of 2.5 mL / kg body weight in the same manner .	[ "In", "addition", ",", "one", "control", "group", "(", "4", "female", "monkeys", ")", "received", "the", "vehicle", "at", "an", "application", "volume", "of", "2.5", "mL", "/", "kg", "body", "weight", "in", "the", "same", "manner", "and", "another", "control", "group", "(", "4", "female", "monkeys", ")", "received", "0.9", "%", "(", "w", "/", "v", ")", "sodium", "chloride", "solution", "at", "an", "application", "volume", "of", "2.5", "mL", "/", "kg", "body", "weight", "in", "the", "same", "manner", "." ]	[ "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Due to the cessation of development of COMPOUND_XXX , only selected target organs in female animals at the end of the treatment period were examined histologically .	[ "Due", "to", "the", "cessation", "of", "development", "of", "COMPOUND_XXX", ",", "only", "selected", "target", "organs", "in", "female", "animals", "at", "the", "end", "of", "the", "treatment", "period", "were", "examined", "histologically", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Following a 4 - week recovery period , thyroid , thymic , and testicular changes were considered to be fully reversible whereas lymph node and epididymal changes were partially reversible .	[ "Following", "a", "4", "-", "week", "recovery", "period", ",", "thyroid", ",", "thymic", ",", "and", "testicular", "changes", "were", "considered", "to", "be", "fully", "reversible", "whereas", "lymph", "node", "and", "epididymal", "changes", "were", "partially", "reversible", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	At gross pathology four 40 mg / kg / d males showed minimal to mild , multifocal beige discoloration of the kidney .	[ "At", "gross", "pathology", "four", "40", "mg", "/", "kg", "/", "d", "males", "showed", "minimal", "to", "mild", ",", "multifocal", "beige", "discoloration", "of", "the", "kidney", "." ]	[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "B-SEX", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN" ]	[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 5, 0, 0, 0, 0, 0, 8, 9, 9, 0, 0, 10, 11 ]
NO_PRETOX_REL	At the genomic level , COMPOUND_XXX did not induce any noteworthy transcriptional changes in heart or skeletal muscle at 40 or 80 mg / kg after treatment for 3 or 28 days .	[ "At", "the", "genomic", "level", ",", "COMPOUND_XXX", "did", "not", "induce", "any", "noteworthy", "transcriptional", "changes", "in", "heart", "or", "skeletal", "muscle", "at", "40", "or", "80", "mg", "/", "kg", "after", "treatment", "for", "3", "or", "28", "days", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	At the end of recovery , high dose ( 30 mg / kg ) recovery animals had the same incidence and degree of cytoplasmic vacuolation of interstitital cells as the main kill animals of this dose level .	[ "At", "the", "end", "of", "recovery", ",", "high", "dose", "(", "30", "mg", "/", "kg", ")", "recovery", "animals", "had", "the", "same", "incidence", "and", "degree", "of", "cytoplasmic", "vacuolation", "of", "interstitital", "cells", "as", "the", "main", "kill", "animals", "of", "this", "dose", "level", "." ]	[ "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The determination of a maximum tolerated dose ( MTD ) in this study is mainly based on the finding that body weight gain and survival of the monkeys were not affected at all three dose levels .	[ "The", "determination", "of", "a", "maximum", "tolerated", "dose", "(", "MTD", ")", "in", "this", "study", "is", "mainly", "based", "on", "the", "finding", "that", "body", "weight", "gain", "and", "survival", "of", "the", "monkeys", "were", "not", "affected", "at", "all", "three", "dose", "levels", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Individual animals presented with slight to marked decreases in white blood cell counts .	[ "Individual", "animals", "presented", "with", "slight", "to", "marked", "decreases", "in", "white", "blood", "cell", "counts", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 1, 0, 2, 6, 6, 6, 0 ]
PRETOX_REL	Diarrhea and missing defecation were incidental findings deemed unrelated to treatment with the test substance .	[ "Diarrhea", "and", "missing", "defecation", "were", "incidental", "findings", "deemed", "unrelated", "to", "treatment", "with", "the", "test", "substance", "." ]	[ "B-FINDING", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 8, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Thereafter the mean body weight gain of males was comparable between the treated and the control group .	[ "Thereafter", "the", "mean", "body", "weight", "gain", "of", "males", "was", "comparable", "between", "the", "treated", "and", "the", "control", "group", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL	Food consumption , ophthalmology , clinical chemistry and organ weight investigations did not reveal any treatment - related findings .	[ "Food", "consumption", ",", "ophthalmology", ",", "clinical", "chemistry", "and", "organ", "weight", "investigations", "did", "not", "reveal", "any", "treatment", "-", "related", "findings", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	At the terminal necropsy , organ weight changes included increased heart weights in males at doses : ; : : : 15 mg / kg / day and in females at 50 mg / kg / day ; decreased spleen weights in males at doses : ; : : : 15 mg!kg / day ; and at 50 mg / kg / day , increased adrenal weights in both sexes ; increased liver and thyroid weights in males ; increased ovary weights and decreased pituitary weights in females and decreased testis weights .	[ "At", "the", "terminal", "necropsy", ",", "organ", "weight", "changes", "included", "increased", "heart", "weights", "in", "males", "at", "doses", ":", ";", ":", ":", ":", "15", "mg", "/", "kg", "/", "day", "and", "in", "females", "at", "50", "mg", "/", "kg", "/", "day", ";", "decreased", "spleen", "weights", "in", "males", "at", "doses", ":", ";", ":", ":", ":", "15", "mg!kg", "/", "day", ";", "and", "at", "50", "mg", "/", "kg", "/", "day", ",", "increased", "adrenal", "weights", "in", "both", "sexes", ";", "increased", "liver", "and", "thyroid", "weights", "in", "males", ";", "increased", "ovary", "weights", "and", "decreased", "pituitary", "weights", "in", "females", "and", "decreased", "testis", "weights", "." ]	[ "O", "O", "O", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "I-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O" ]	[ 0, 0, 0, 0, 0, 10, 2, 1, 0, 1, 10, 2, 0, 5, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 1, 10, 2, 0, 5, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 1, 10, 2, 0, 5, 7, 0, 1, 10, 0, 10, 2, 0, 5, 0, 1, 10, 2, 0, 1, 10, 2, 0, 5, 0, 1, 10, 2, 0 ]
PRETOX_REL	CONCLUSION In conclusion , the administration of COMPOUND_XXX by daily oral gavage for 3 or 10 days at dose levels of 0 , 50 mg / kg / day and 200 mg / kg / day resulted in clinical signs of dehydration and fur staining red , adverse reductions in body weight gain with associated reduced food consumption , minor hematology ( prolonged PT ) , biochemical ( increased BUN ) , significant urinalysis changes ( increased urinary protein and occult blood , glycosuria and polyuria ) , with associated macroscopic ( pale discolouration in medulla or corticomedullary junction ) and microscopic changes ( tubular degeneration / regeneration in the outer medulla ) in the kidney of rats treated with 200 mg / kg / day COMPOUND_XXX .	[ "CONCLUSION", "In", "conclusion", ",", "the", "administration", "of", "COMPOUND_XXX", "by", "daily", "oral", "gavage", "for", "3", "or", "10", "days", "at", "dose", "levels", "of", "0", ",", "50", "mg", "/", "kg", "/", "day", "and", "200", "mg", "/", "kg", "/", "day", "resulted", "in", "clinical", "signs", "of", "dehydration", "and", "fur", "staining", "red", ",", "adverse", "reductions", "in", "body", "weight", "gain", "with", "associated", "reduced", "food", "consumption", ",", "minor", "hematology", "(", "prolonged", "PT", ")", ",", "biochemical", "(", "increased", "BUN", ")", ",", "significant", "urinalysis", "changes", "(", "increased", "urinary", "protein", "and", "occult", "blood", ",", "glycosuria", "and", "polyuria", ")", ",", "with", "associated", "macroscopic", "(", "pale", "discolouration", "in", "medulla", "or", "corticomedullary", "junction", ")", "and", "microscopic", "changes", "(", "tubular", "degeneration", "/", "regeneration", "in", "the", "outer", "medulla", ")", "in", "the", "kidney", "of", "rats", "treated", "with", "200", "mg", "/", "kg", "/", "day", "COMPOUND_XXX", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-SPECIMEN", "O", "O", "O", "B-SPECIMEN", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 8, 0, 8, 9, 9, 0, 0, 1, 0, 2, 6, 6, 0, 0, 1, 2, 6, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 1, 2, 0, 0, 0, 2, 1, 0, 1, 2, 6, 0, 2, 6, 0, 8, 0, 8, 0, 0, 0, 0, 0, 0, 8, 9, 0, 10, 0, 10, 11, 0, 0, 0, 0, 0, 8, 9, 9, 9, 0, 0, 0, 10, 0, 0, 0, 10, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0 ]
NO_PRETOX_REL	An additional group of rats ( 10 / sex ) received vehicle ( Purified Water , USP ) at an equivalent dosing volume ( 10 mL / kg ) and served as a control .	[ "An", "additional", "group", "of", "rats", "(", "10", "/", "sex", ")", "received", "vehicle", "(", "Purified", "Water", ",", "USP", ")", "at", "an", "equivalent", "dosing", "volume", "(", "10", "mL", "/", "kg", ")", "and", "served", "as", "a", "control", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The high dose of 375 μmol Gd / kg bw .	[ "The", "high", "dose", "of", "375", "μmol", "Gd", "/", "kg", "bw", "." ]	[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 15, 16, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	One animal dosed at 80 mg / kg bw .	[ "One", "animal", "dosed", "at", "80", "mg", "/", "kg", "bw", "." ]	[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	Toxicokinetic data indicate a moderately fast absorption of the test compound after intragastric administration , a minor to moderate accumulation potential of the drug after daily administration and a higher systemic exposure ( AUC ( 0 - t last ) ) in female compared to male Beagle dogs .	[ "Toxicokinetic", "data", "indicate", "a", "moderately", "fast", "absorption", "of", "the", "test", "compound", "after", "intragastric", "administration", ",", "a", "minor", "to", "moderate", "accumulation", "potential", "of", "the", "drug", "after", "daily", "administration", "and", "a", "higher", "systemic", "exposure", "(", "AUC", "(", "0", "-", "t", "last", ")", ")", "in", "female", "compared", "to", "male", "Beagle", "dogs", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	In the current study , in - life and terminal data collection included , clinical observations , body weight , food consumption , clinical pathology , full necropsy , organ weight analysis and comprehensive histopathology of selected tissues .	[ "In", "the", "current", "study", ",", "in", "-", "life", "and", "terminal", "data", "collection", "included", ",", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "clinical", "pathology", ",", "full", "necropsy", ",", "organ", "weight", "analysis", "and", "comprehensive", "histopathology", "of", "selected", "tissues", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	COMPOUND_XXX has shown a predictable cholinomimetic profile in the one year chronic toxicity studies in the rat .	[ "COMPOUND_XXX", "has", "shown", "a", "predictable", "cholinomimetic", "profile", "in", "the", "one", "year", "chronic", "toxicity", "studies", "in", "the", "rat", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	A consequence of the hyperostosis is the increased hemopoiesis in the spleen in the high dose group .	[ "A", "consequence", "of", "the", "hyperostosis", "is", "the", "increased", "hemopoiesis", "in", "the", "spleen", "in", "the", "high", "dose", "group", "." ]	[ "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 8, 0, 0, 8, 9, 0, 0, 10, 0, 0, 12, 13, 13, 0 ]
PRETOX_REL	Local reactions were found in both control and compound - treated group indicating mechanical irritation .	[ "Local", "reactions", "were", "found", "in", "both", "control", "and", "compound", "-", "treated", "group", "indicating", "mechanical", "irritation", "." ]	[ "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-FINDING", "I-FINDING", "O" ]	[ 8, 9, 0, 0, 0, 0, 12, 13, 13, 13, 13, 13, 0, 8, 9, 0 ]
PRETOX_REL	Clinical chemistry alterations noted just prior to sacrifice included moderate hyponatremia , marked hypochloridemia , hyperproteinemia , hypoglycemia , increased serum triglyceride concentration and moderate azotemia / uremia .	[ "Clinical", "chemistry", "alterations", "noted", "just", "prior", "to", "sacrifice", "included", "moderate", "hyponatremia", ",", "marked", "hypochloridemia", ",", "hyperproteinemia", ",", "hypoglycemia", ",", "increased", "serum", "triglyceride", "concentration", "and", "moderate", "azotemia", "/", "uremia", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-FINDING", "O", "B-FINDING", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 8, 0, 8, 0, 8, 0, 1, 10, 2, 6, 0, 0, 8, 0, 8, 0 ]
PRETOX_REL	Food Consumption : Slight reductions in food consumption were observed in females given 600 mg / kg / day .	[ "Food", "Consumption", ":", "Slight", "reductions", "in", "food", "consumption", "were", "observed", "in", "females", "given", "600", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 1, 0, 2, 6, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	The deaths were not considered treatment - related .	[ "The", "deaths", "were", "not", "considered", "treatment", "-", "related", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Likely due to effects of COMPOUND_XXX on fast renewal cells division cycle by Met receptor tyrosine kinase inhibition and associated changes : - disorganisations of the intestinal epithelium and / or the increase in the apoptotic bodies number were noted in both sexes at 40 mg / kg only with a severity and incidence more marked in dosed - females .	[ "Likely", "due", "to", "effects", "of", "COMPOUND_XXX", "on", "fast", "renewal", "cells", "division", "cycle", "by", "Met", "receptor", "tyrosine", "kinase", "inhibition", "and", "associated", "changes", ":", "-", "disorganisations", "of", "the", "intestinal", "epithelium", "and", "/", "or", "the", "increase", "in", "the", "apoptotic", "bodies", "number", "were", "noted", "in", "both", "sexes", "at", "40", "mg", "/", "kg", "only", "with", "a", "severity", "and", "incidence", "more", "marked", "in", "dosed", "-", "females", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 10, 11, 0, 0, 0, 0, 1, 0, 0, 8, 9, 0, 0, 0, 0, 5, 7, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The compound could be injected by the intravenous route even in group IV for more than 4 weeks .	[ "The", "compound", "could", "be", "injected", "by", "the", "intravenous", "route", "even", "in", "group", "IV", "for", "more", "than", "4", "weeks", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Several animals also showed slight skin erythema at the sites covered by FixomuiiR , probably due to the daily removal procedures .	[ "Several", "animals", "also", "showed", "slight", "skin", "erythema", "at", "the", "sites", "covered", "by", "FixomuiiR", ",", "probably", "due", "to", "the", "daily", "removal", "procedures", "." ]	[ "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The relative exposure of COMPOUND_XXX to Ganciclovir was only 1 - 2 % and the relative peak concentrations were only 6 - 13 % .	[ "The", "relative", "exposure", "of", "COMPOUND_XXX", "to", "Ganciclovir", "was", "only", "1", "-", "2", "%", "and", "the", "relative", "peak", "concentrations", "were", "only", "6", "-", "13", "%", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	All test article - treated animals exhibited measurable concentrations of COMPOUND_XXX .	[ "All", "test", "article", "-", "treated", "animals", "exhibited", "measurable", "concentrations", "of", "COMPOUND_XXX", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In - life effects included fecal changes ( soft , reduced and absent feces ) in both sexes at 150 ~ 100 mg / kg / day with increased incidence in the females .	[ "In", "-", "life", "effects", "included", "fecal", "changes", "(", "soft", ",", "reduced", "and", "absent", "feces", ")", "in", "both", "sexes", "at", "150", "~", "100", "mg", "/", "kg", "/", "day", "with", "increased", "incidence", "in", "the", "females", "." ]	[ "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "B-SPECIMEN", "O", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-SEX", "O" ]	[ 0, 0, 0, 0, 0, 8, 9, 0, 8, 0, 8, 0, 8, 10, 0, 0, 5, 7, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 5, 0 ]
NO_PRETOX_REL	The later is an indirect consequence of the inhibition of PDGFR which also involves insuline - like - growth factor 1 ( IGF1 ) / phosphoinositid -3-kinase ( Pi3K ) pathway .	[ "The", "later", "is", "an", "indirect", "consequence", "of", "the", "inhibition", "of", "PDGFR", "which", "also", "involves", "insuline", "-", "like", "-", "growth", "factor", "1", "(", "IGF1", ")", "/", "phosphoinositid", "-3-kinase", "(", "Pi3K", ")", "pathway", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Microscopic examinations were performed on gross lesions and protocol - specified set of tissues from all animals .	[ "Microscopic", "examinations", "were", "performed", "on", "gross", "lesions", "and", "protocol", "-", "specified", "set", "of", "tissues", "from", "all", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	This effect was reversible No compound - related effects were noted in water consumption and in ophthalmoscopical examination .	[ "This", "effect", "was", "reversible", "No", "compound", "-", "related", "effects", "were", "noted", "in", "water", "consumption", "and", "in", "ophthalmoscopical", "examination", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Findings observed in animals exposed to COMPOUND_XXX at a daily dose of 10 umol / kg bw .	[ "Findings", "observed", "in", "animals", "exposed", "to", "COMPOUND_XXX", "at", "a", "daily", "dose", "of", "10", "umol", "/", "kg", "bw", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	Systemic exposure decreased over proportionally with decreasing dose .	[ "Systemic", "exposure", "decreased", "over", "proportionally", "with", "decreasing", "dose", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Alterations of laboratory parameters are considered to be secondary effects due to inflammatory processes in the lung .	[ "Alterations", "of", "laboratory", "parameters", "are", "considered", "to", "be", "secondary", "effects", "due", "to", "inflammatory", "processes", "in", "the", "lung", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 0 ]
NO_PRETOX_REL	Histological examination performed on the ovaries , testes and epididymes ( with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure ) of the animals of the 225 mg / kg / group and the control group did not evidence any toxicological pathomorphological lesions .	[ "Histological", "examination", "performed", "on", "the", "ovaries", ",", "testes", "and", "epididymes", "(", "with", "special", "emphasis", "on", "stages", "of", "spermatogenesis", "and", "histopathology", "of", "interstitial", "testicular", "cell", "structure", ")", "of", "the", "animals", "of", "the", "225", "mg", "/", "kg", "/", "group", "and", "the", "control", "group", "did", "not", "evidence", "any", "toxicological", "pathomorphological", "lesions", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	With the exception of several animals of the low dose group , all dogs were exposed to the test compound over the entire 24 h dosing interval .	[ "With", "the", "exception", "of", "several", "animals", "of", "the", "low", "dose", "group", ",", "all", "dogs", "were", "exposed", "to", "the", "test", "compound", "over", "the", "entire", "24", "h", "dosing", "interval", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	In addition , heart and skeletal muscle were sampled for gene expression analysis and determination of COMPOUND_XXX tissue concentrations ( about 3 hours after 28th dose ) .	[ "In", "addition", ",", "heart", "and", "skeletal", "muscle", "were", "sampled", "for", "gene", "expression", "analysis", "and", "determination", "of", "COMPOUND_XXX", "tissue", "concentrations", "(", "about", "3", "hours", "after", "28th", "dose", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Signs of recovery could be detected in some animals .	[ "Signs", "of", "recovery", "could", "be", "detected", "in", "some", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Post-mortem investigations included organ weights , macroscopic and microscopic examinations .	[ "Post-mortem", "investigations", "included", "organ", "weights", ",", "macroscopic", "and", "microscopic", "examinations", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Due to the distinct pharmacological activity of the compound even at the low dose , a NOEL was not identified .	[ "Due", "to", "the", "distinct", "pharmacological", "activity", "of", "the", "compound", "even", "at", "the", "low", "dose", ",", "a", "NOEL", "was", "not", "identified", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	One high - dose female ( no. 4501 ) was sacrificed due to poor condition on day 13 .	[ "One", "high", "-", "dose", "female", "(", "no.", "4501", ")", "was", "sacrificed", "due", "to", "poor", "condition", "on", "day", "13", "." ]	[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O" ]	[ 0, 15, 16, 16, 5, 0, 0, 0, 0, 0, 8, 0, 0, 8, 9, 0, 0, 0, 0 ]
NO_PRETOX_REL	After -4 weeks , the high dose was reduced from 20 mg / kg / day to 10 mg / kg / day .	[ "After", "-4", "weeks", ",", "the", "high", "dose", "was", "reduced", "from", "20", "mg", "/", "kg", "/", "day", "to", "10", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 3, 4, 4, 4, 4, 4, 0 ]
PRETOX_REL	Anemia and atrophy in the bone marrow and lymphatic organs were considered to be associated with the pharmacological action of COMPOUND_XXX .	[ "Anemia", "and", "atrophy", "in", "the", "bone", "marrow", "and", "lymphatic", "organs", "were", "considered", "to", "be", "associated", "with", "the", "pharmacological", "action", "of", "COMPOUND_XXX", "." ]	[ "B-FINDING", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 8, 0, 8, 0, 0, 10, 11, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	At 1.2 mg / kg , the AUC and Cmax were 220 and 193 ng · h / mL and 185 and 169 ng / mL for males and females , respectively ( day 85 ) .	[ "At", "1.2", "mg", "/", "kg", ",", "the", "AUC", "and", "Cmax", "were", "220", "and", "193", "ng", "·", "h", "/", "mL", "and", "185", "and", "169", "ng", "/", "mL", "for", "males", "and", "females", ",", "respectively", "(", "day", "85", ")", "." ]	[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

The relevance of the decreased liver weight in high dose males at the end of the treatment period is unclear .

[ "The", "relevance", "of", "the", "decreased", "liver", "weight", "in", "high", "dose", "males", "at", "the", "end", "of", "the", "treatment", "period", "is", "unclear", "." ]

[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 1, 10, 2, 0, 15, 16, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

There was bright yellow urine in the bladder .

[ "There", "was", "bright", "yellow", "urine", "in", "the", "bladder", "." ]

[ "O", "O", "B-FINDING", "I-FINDING", "B-SPECIMEN", "O", "O", "B-SPECIMEN", "O" ]

[ 0, 0, 8, 9, 10, 0, 0, 10, 0 ]

NO_PRETOX_REL

Dogs were constituted within 4 different groups receiving oral doses of placebo ( control group , group 1 ) , 5 ( group 2 ) , 15 ( group 3 ) and 60 or 70 ( group 4 ) mg / kg / day for 52 weeks .

[ "Dogs", "were", "constituted", "within", "4", "different", "groups", "receiving", "oral", "doses", "of", "placebo", "(", "control", "group", ",", "group", "1", ")", ",", "5", "(", "group", "2", ")", ",", "15", "(", "group", "3", ")", "and", "60", "or", "70", "(", "group", "4", ")", "mg", "/", "kg", "/", "day", "for", "52", "weeks", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 12, 13, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Tissues with high mitotic activity are a known target for compounds of this class .

[ "Tissues", "with", "high", "mitotic", "activity", "are", "a", "known", "target", "for", "compounds", "of", "this", "class", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The mean values of these groups on day 5 were 2 - 4 % lower than those at the beginning of the treatment .

[ "The", "mean", "values", "of", "these", "groups", "on", "day", "5", "were", "2", "-", "4", "%", "lower", "than", "those", "at", "the", "beginning", "of", "the", "treatment", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

A reversal of these changes was observed during the recovery period .

[ "A", "reversal", "of", "these", "changes", "was", "observed", "during", "the", "recovery", "period", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The purpose of this nonclinical laboratory study was to establish the toxicologic effects of COMPOUND_XXX , a potent inhibitor of the Bcr - Abl tyrosine kinases , foreseen primarily in the treatment of chronic myeloid leukemia , when administered to dogs for 4 weeks .

[ "The", "purpose", "of", "this", "nonclinical", "laboratory", "study", "was", "to", "establish", "the", "toxicologic", "effects", "of", "COMPOUND_XXX", ",", "a", "potent", "inhibitor", "of", "the", "Bcr", "-", "Abl", "tyrosine", "kinases", ",", "foreseen", "primarily", "in", "the", "treatment", "of", "chronic", "myeloid", "leukemia", ",", "when", "administered", "to", "dogs", "for", "4", "weeks", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

The decrease in erythron mass and altered erythroid indices were attributed to a recrudescence of the Plasmodium sp causing increased red cell parasitism and destruction .

[ "The", "decrease", "in", "erythron", "mass", "and", "altered", "erythroid", "indices", "were", "attributed", "to", "a", "recrudescence", "of", "the", "Plasmodium", "sp", "causing", "increased", "red", "cell", "parasitism", "and", "destruction", "." ]

[ "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-FINDING", "O", "B-FINDING", "O" ]

[ 0, 1, 0, 2, 6, 0, 8, 9, 9, 0, 0, 0, 0, 8, 9, 9, 9, 9, 0, 1, 0, 10, 8, 0, 8, 0 ]

NO_PRETOX_REL

Two patches were applied at each dosing in groups 1 , 3 and 4 , and one patch was applied in group 2 .

[ "Two", "patches", "were", "applied", "at", "each", "dosing", "in", "groups", "1", ",", "3", "and", "4", ",", "and", "one", "patch", "was", "applied", "in", "group", "2", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]

PRETOX_REL

Other signs observed only in the Mid-High and High dose groups were excessive grooming , decreased locomotor activity , ataxia and flattened body position .

[ "Other", "signs", "observed", "only", "in", "the", "Mid-High", "and", "High", "dose", "groups", "were", "excessive", "grooming", ",", "decreased", "locomotor", "activity", ",", "ataxia", "and", "flattened", "body", "position", "." ]

[ "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-FINDING", "I-FINDING", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]

[ 0, 0, 0, 0, 0, 0, 12, 13, 13, 13, 13, 0, 8, 9, 0, 1, 2, 6, 0, 8, 0, 8, 9, 9, 0 ]

NO_PRETOX_REL

In hematology including coagulation , clinical chemistry and urinalysis no treatment - related alterations were seen .

[ "In", "hematology", "including", "coagulation", ",", "clinical", "chemistry", "and", "urinalysis", "no", "treatment", "-", "related", "alterations", "were", "seen", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

In addition , hypertrophy of acinar cells in salivary and lacrimal glands were observed from the low dose upwards .

[ "In", "addition", ",", "hypertrophy", "of", "acinar", "cells", "in", "salivary", "and", "lacrimal", "glands", "were", "observed", "from", "the", "low", "dose", "upwards", "." ]

[ "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O" ]

[ 0, 0, 0, 8, 0, 0, 0, 0, 10, 0, 10, 11, 0, 0, 0, 0, 15, 16, 0, 0 ]

NO_PRETOX_REL

Blood samples for toxicokinetics were taken on the first day of dosing and in week I3 and 26 of dosing .

[ "Blood", "samples", "for", "toxicokinetics", "were", "taken", "on", "the", "first", "day", "of", "dosing", "and", "in", "week", "I3", "and", "26", "of", "dosing", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Urinalysis revealed a decrease in urinary volume accompanied by an increase in the urine specific gravity and urine creatinine concentrations , and a mild increase in urinary protein , urobilinogen and total leukocytes .

[ "Urinalysis", "revealed", "a", "decrease", "in", "urinary", "volume", "accompanied", "by", "an", "increase", "in", "the", "urine", "specific", "gravity", "and", "urine", "creatinine", "concentrations", ",", "and", "a", "mild", "increase", "in", "urinary", "protein", ",", "urobilinogen", "and", "total", "leukocytes", "." ]

[ "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]

[ 0, 0, 0, 1, 0, 2, 6, 0, 0, 0, 1, 0, 0, 2, 6, 6, 0, 2, 6, 0, 0, 0, 0, 0, 1, 0, 2, 6, 0, 2, 0, 2, 6, 0 ]

NO_PRETOX_REL

These findings were consistent with those from earlier toxicity studies with COMPOUND_XXX , occurred with similar incidence and severity between the two synthetic lots , and were associated with a similar toxicokinetic profile .

[ "These", "findings", "were", "consistent", "with", "those", "from", "earlier", "toxicity", "studies", "with", "COMPOUND_XXX", ",", "occurred", "with", "similar", "incidence", "and", "severity", "between", "the", "two", "synthetic", "lots", ",", "and", "were", "associated", "with", "a", "similar", "toxicokinetic", "profile", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

COMPOUND_XXX and COMPOUND_ZZZ were detected in all treated animals indicating that the dogs were exposed to the compounds ( parent and its metabolite ) suggesting drug absorption at all dose levels .

[ "COMPOUND_XXX", "and", "COMPOUND_ZZZ", "were", "detected", "in", "all", "treated", "animals", "indicating", "that", "the", "dogs", "were", "exposed", "to", "the", "compounds", "(", "parent", "and", "its", "metabolite", ")", "suggesting", "drug", "absorption", "at", "all", "dose", "levels", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

In addition , a secondary concentration peak , indicating enterohepatic recirculation of the drug , was observed in several animals .

[ "In", "addition", ",", "a", "secondary", "concentration", "peak", ",", "indicating", "enterohepatic", "recirculation", "of", "the", "drug", ",", "was", "observed", "in", "several", "animals", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Mean COMPOUND_XXX concentrations in the duodenal mucosa of 2560 and 25400 ng / g tissue and in the duodenal content of 6430 and 62400 ng / g at 20 and 180 mg / kg , respectively , appeared to increase roughly proportionally with the dose , but individual values showed a high inter-animal variability .

[ "Mean", "COMPOUND_XXX", "concentrations", "in", "the", "duodenal", "mucosa", "of", "2560", "and", "25400", "ng", "/", "g", "tissue", "and", "in", "the", "duodenal", "content", "of", "6430", "and", "62400", "ng", "/", "g", "at", "20", "and", "180", "mg", "/", "kg", ",", "respectively", ",", "appeared", "to", "increase", "roughly", "proportionally", "with", "the", "dose", ",", "but", "individual", "values", "showed", "a", "high", "inter-animal", "variability", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Post-mortem examinations revealed neither systemic nor local effects attributable to the dermal treatment with the test item or its placebo formulation .

[ "Post-mortem", "examinations", "revealed", "neither", "systemic", "nor", "local", "effects", "attributable", "to", "the", "dermal", "treatment", "with", "the", "test", "item", "or", "its", "placebo", "formulation", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

XXXXX ) , of identical design , that was performed using two dosage levels of D6 ( also known as COMPOUND_XXX ) , a minor metabolite of COMPOUND_XXX in rats .

[ "XXXXX", ")", ",", "of", "identical", "design", ",", "that", "was", "performed", "using", "two", "dosage", "levels", "of", "D6", "(", "also", "known", "as", "COMPOUND_XXX", ")", ",", "a", "minor", "metabolite", "of", "COMPOUND_XXX", "in", "rats", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The NOAEL ( No Observed Adverse Effect Level ) is considered to be 0.01 mg / kg / day .

[ "The", "NOAEL", "(", "No", "Observed", "Adverse", "Effect", "Level", ")", "is", "considered", "to", "be", "0.01", "mg", "/", "kg", "/", "day", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]

PRETOX_REL

In females , the mean total protein concentration was lower ( - 9 % ) and a tendency towards higher values was noted in alkaline phosphatase activities ( +32 % ) .

[ "In", "females", ",", "the", "mean", "total", "protein", "concentration", "was", "lower", "(", "-", "9", "%", ")", "and", "a", "tendency", "towards", "higher", "values", "was", "noted", "in", "alkaline", "phosphatase", "activities", "(", "+32", "%", ")", "." ]

[ "O", "B-SEX", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "O" ]

[ 0, 5, 0, 0, 2, 6, 6, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 2, 6, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

No changes were seen in body weight , or food and water consumption of female animals at 25 mg / kg .

[ "No", "changes", "were", "seen", "in", "body", "weight", ",", "or", "food", "and", "water", "consumption", "of", "female", "animals", "at", "25", "mg", "/", "kg", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0 ]

NO_PRETOX_REL

Protocol - specified organs were weighed and tissues were collected , processed and microscopically examined on all animals .

[ "Protocol", "-", "specified", "organs", "were", "weighed", "and", "tissues", "were", "collected", ",", "processed", "and", "microscopically", "examined", "on", "all", "animals", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Test article - related microscopic changes in the spleen were decreased cellularity , lymphocytic , in all males and 9/10 females at 0.9 mglkg with decreased cellularity , red pulp in 2110 males and increased extramedullary hematopoiesis in all females at 0.9 mg / kg and 9/10 females at both 0.05 and 0.3 mglkg .

[ "Test", "article", "-", "related", "microscopic", "changes", "in", "the", "spleen", "were", "decreased", "cellularity", ",", "lymphocytic", ",", "in", "all", "males", "and", "9/10", "females", "at", "0.9", "mglkg", "with", "decreased", "cellularity", ",", "red", "pulp", "in", "2110", "males", "and", "increased", "extramedullary", "hematopoiesis", "in", "all", "females", "at", "0.9", "mg", "/", "kg", "and", "9/10", "females", "at", "both", "0.05", "and", "0.3", "mglkg", "." ]

[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 8, 9, 0, 0, 10, 0, 1, 2, 0, 2, 0, 0, 0, 5, 0, 0, 5, 0, 3, 4, 0, 1, 2, 0, 8, 9, 0, 0, 5, 0, 8, 9, 9, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 5, 0, 0, 3, 4, 4, 4, 0 ]

PRETOX_REL

Changes in cholesterol , triglycerides and alkaline phosphatase were additional evidences of liver metabolism dysfunction with both test - items .

[ "Changes", "in", "cholesterol", ",", "triglycerides", "and", "alkaline", "phosphatase", "were", "additional", "evidences", "of", "liver", "metabolism", "dysfunction", "with", "both", "test", "-", "items", "." ]

[ "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-SPECIMEN", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O" ]

[ 1, 0, 2, 0, 2, 0, 2, 6, 0, 0, 0, 0, 10, 8, 9, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

+ EN ATTENTE BIOMARQUEURS , with corresponding Cmax and AUC values in male / female rats of 1170/2140 ng / mL and 14600 / 18700 ng.h / mL , respectively .

[ "+", "EN", "ATTENTE", "BIOMARQUEURS", ",", "with", "corresponding", "Cmax", "and", "AUC", "values", "in", "male", "/", "female", "rats", "of", "1170/2140", "ng", "/", "mL", "and", "14600", "/", "18700", "ng.h", "/", "mL", ",", "respectively", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Plasma levels were above the limit of quantification during the complete dosing interval .

[ "Plasma", "levels", "were", "above", "the", "limit", "of", "quantification", "during", "the", "complete", "dosing", "interval", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The following investigations were performed : mortality , clinical signs , body weight , food consumption , plasma concentrations of COMPOUND_XXX ( before necropsy ) , macroscopic examination and histopathology of selected organs ( jejunum , ileum , colon , liver , pancreas and spleen ) .

[ "The", "following", "investigations", "were", "performed", ":", "mortality", ",", "clinical", "signs", ",", "body", "weight", ",", "food", "consumption", ",", "plasma", "concentrations", "of", "COMPOUND_XXX", "(", "before", "necropsy", ")", ",", "macroscopic", "examination", "and", "histopathology", "of", "selected", "organs", "(", "jejunum", ",", "ileum", ",", "colon", ",", "liver", ",", "pancreas", "and", "spleen", ")", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

No treatment - related effects were observed on food consumption .

[ "No", "treatment", "-", "related", "effects", "were", "observed", "on", "food", "consumption", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

The one high - dose male recovery animal ( the other recovery animal died during the study ) showed increased liver weight and altered liver histology that did not show evidence of recovery .

[ "The", "one", "high", "-", "dose", "male", "recovery", "animal", "(", "the", "other", "recovery", "animal", "died", "during", "the", "study", ")", "showed", "increased", "liver", "weight", "and", "altered", "liver", "histology", "that", "did", "not", "show", "evidence", "of", "recovery", "." ]

[ "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 15, 16, 16, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 10, 2, 0, 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

The severe skin erythema appeared from approximately day 9 .

[ "The", "severe", "skin", "erythema", "appeared", "from", "approximately", "day", "9", "." ]

[ "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 8, 9, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

In another female of this dose group mild acute multifocal bilateral hemorrhages were seen in the corpora lutea .

[ "In", "another", "female", "of", "this", "dose", "group", "mild", "acute", "multifocal", "bilateral", "hemorrhages", "were", "seen", "in", "the", "corpora", "lutea", "." ]

[ "O", "O", "B-SEX", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]

[ 0, 0, 5, 0, 0, 12, 13, 0, 0, 8, 9, 9, 0, 0, 0, 0, 10, 11, 0 ]

NO_PRETOX_REL

Approximately proportional increases in COMPOUND_XXX plasma concentrations were seen with increased dose .

[ "Approximately", "proportional", "increases", "in", "COMPOUND_XXX", "plasma", "concentrations", "were", "seen", "with", "increased", "dose", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

At necropsy light yellow discoloration of the xiphoid cartilage was observed grossly in both male and female rats , and bright yellow urine was present in the bladder .

[ "At", "necropsy", "light", "yellow", "discoloration", "of", "the", "xiphoid", "cartilage", "was", "observed", "grossly", "in", "both", "male", "and", "female", "rats", ",", "and", "bright", "yellow", "urine", "was", "present", "in", "the", "bladder", "." ]

[ "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O", "O", "B-FINDING", "I-FINDING", "B-SPECIMEN", "O", "O", "O", "O", "B-SPECIMEN", "O" ]

[ 0, 0, 8, 9, 9, 0, 0, 10, 11, 0, 0, 0, 0, 0, 5, 7, 7, 0, 0, 0, 8, 9, 10, 0, 0, 0, 0, 10, 0 ]

PRETOX_REL

Serum creatinine and BUN were slightly increased in female rats .

[ "Serum", "creatinine", "and", "BUN", "were", "slightly", "increased", "in", "female", "rats", "." ]

[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SEX", "O", "O" ]

[ 2, 6, 0, 2, 0, 0, 1, 0, 5, 0, 0 ]

PRETOX_REL

Clinical findings prior to death were apathy , emaciation , prone , lateral or supine position , disturbances in gait and vomiting

[ "Clinical", "findings", "prior", "to", "death", "were", "apathy", ",", "emaciation", ",", "prone", ",", "lateral", "or", "supine", "position", ",", "disturbances", "in", "gait", "and", "vomiting" ]

[ "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING" ]

[ 0, 0, 0, 0, 0, 0, 8, 0, 8, 0, 8, 9, 9, 9, 9, 9, 0, 8, 9, 9, 0, 8 ]

NO_PRETOX_REL

Control animals similarly received the vehicle for the test item ( Millipore water ) at a dosage volume of 5 mL / kg .

[ "Control", "animals", "similarly", "received", "the", "vehicle", "for", "the", "test", "item", "(", "Millipore", "water", ")", "at", "a", "dosage", "volume", "of", "5", "mL", "/", "kg", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Additionally , a slight to moderate increase in severity of the hyaline droplet content in the proximal convoluted tubules of 4/5 males was observed .

[ "Additionally", ",", "a", "slight", "to", "moderate", "increase", "in", "severity", "of", "the", "hyaline", "droplet", "content", "in", "the", "proximal", "convoluted", "tubules", "of", "4/5", "males", "was", "observed", "." ]

[ "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "O", "B-SEX", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 8, 9, 9, 0, 0, 10, 11, 11, 0, 0, 5, 0, 0, 0 ]

NO_PRETOX_REL

Formulation 10 % ( variant 11 ) and On days 1 , 3 and 5 , test items were applicated for 47 hours on the areas of the left flank .

[ "Formulation", "10", "%", "(", "variant", "11", ")", "and", "On", "days", "1", ",", "3", "and", "5", ",", "test", "items", "were", "applicated", "for", "47", "hours", "on", "the", "areas", "of", "the", "left", "flank", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Dose levels up to and including 1000 mg / kg / day were well tolerated .

[ "Dose", "levels", "up", "to", "and", "including", "1000", "mg", "/", "kg", "/", "day", "were", "well", "tolerated", "." ]

[ "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0 ]

PRETOX_REL

Group mean body weight loss was frequently seen in both groups of treated males and for females during treatment at 75 mg / kg / day .

[ "Group", "mean", "body", "weight", "loss", "was", "frequently", "seen", "in", "both", "groups", "of", "treated", "males", "and", "for", "females", "during", "treatment", "at", "75", "mg", "/", "kg", "/", "day", "." ]

[ "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-SEX", "O", "O", "B-SEX", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 2, 6, 1, 0, 0, 0, 0, 12, 13, 0, 0, 5, 0, 0, 5, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

The checks on the body temperatures yielded no changes up to and including group III ( for individual and mean values see appendix of the report ) .

[ "The", "checks", "on", "the", "body", "temperatures", "yielded", "no", "changes", "up", "to", "and", "including", "group", "III", "(", "for", "individual", "and", "mean", "values", "see", "appendix", "of", "the", "report", ")", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

The degenerative testicular changes observed microscopically at all dose levels were considered to be related to the pharmacologic effect of COMPOUND_XXX .

[ "The", "degenerative", "testicular", "changes", "observed", "microscopically", "at", "all", "dose", "levels", "were", "considered", "to", "be", "related", "to", "the", "pharmacologic", "effect", "of", "COMPOUND_XXX", "." ]

[ "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 8, 9, 9, 0, 0, 0, 3, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Females tended to be more affected .

[ "Females", "tended", "to", "be", "more", "affected", "." ]

[ "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Ophthalmoscopy Ophthalmoskopy showed a light center of the yellow spot in one animal from group 3 ( 40 umol / kg bw . )

[ "Ophthalmoscopy", "Ophthalmoskopy", "showed", "a", "light", "center", "of", "the", "yellow", "spot", "in", "one", "animal", "from", "group", "3", "(", "40", "umol", "/", "kg", "bw", ".", ")" ]

[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]

[ 0, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0, 0, 0, 0, 12, 13, 0, 3, 4, 4, 4, 4, 0, 0 ]

NO_PRETOX_REL

d. Ophthalmoscopic findings The individual data for the ophthalmoscopic investigations can be found in the appendix of the report .

[ "d.", "Ophthalmoscopic", "findings", "The", "individual", "data", "for", "the", "ophthalmoscopic", "investigations", "can", "be", "found", "in", "the", "appendix", "of", "the", "report", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Hematology No compound - related effect was observed .

[ "Hematology", "No", "compound", "-", "related", "effect", "was", "observed", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

In conclusion , the oral ( gavage ) administration of COMPOUND_XXX to male rats at dosages of 40 and 80 mg / kg over up to 4 weeks was well tolerated without mortality or clinical signs of toxicity .

[ "In", "conclusion", ",", "the", "oral", "(", "gavage", ")", "administration", "of", "COMPOUND_XXX", "to", "male", "rats", "at", "dosages", "of", "40", "and", "80", "mg", "/", "kg", "over", "up", "to", "4", "weeks", "was", "well", "tolerated", "without", "mortality", "or", "clinical", "signs", "of", "toxicity", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Gravimetric organ findings The absolute and relative organ weights are listed in the appendix of the report in the form of individual values , mean values per group and per sex with their standard deviations , and mean values separately for each sex and for the two sexes together .

[ "Gravimetric", "organ", "findings", "The", "absolute", "and", "relative", "organ", "weights", "are", "listed", "in", "the", "appendix", "of", "the", "report", "in", "the", "form", "of", "individual", "values", ",", "mean", "values", "per", "group", "and", "per", "sex", "with", "their", "standard", "deviations", ",", "and", "mean", "values", "separately", "for", "each", "sex", "and", "for", "the", "two", "sexes", "together", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

In - life and terminal data collection during the treatment and recovery periods included clinical observations , body weight , food consumption , ophthalmic and neurologic examinations , hematology , clinical chemistry , urinalysis and a complete necropsy of all toxicity animals that died during study .

[ "In", "-", "life", "and", "terminal", "data", "collection", "during", "the", "treatment", "and", "recovery", "periods", "included", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "ophthalmic", "and", "neurologic", "examinations", ",", "hematology", ",", "clinical", "chemistry", ",", "urinalysis", "and", "a", "complete", "necropsy", "of", "all", "toxicity", "animals", "that", "died", "during", "study", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

As the table shows , the nutritional state showed no relevant changes up to and including group III .

[ "As", "the", "table", "shows", ",", "the", "nutritional", "state", "showed", "no", "relevant", "changes", "up", "to", "and", "including", "group", "III", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]

NO_PRETOX_REL

The animal No 7088 ( F g r .

[ "The", "animal", "No", "7088", "(", "F", "g", "r", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

of COMPOUND_XXX but remained within the physiological range in all treatment groups .

[ "of", "COMPOUND_XXX", "but", "remained", "within", "the", "physiological", "range", "in", "all", "treatment", "groups", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]

NO_PRETOX_REL

In addition , one control group ( 4 female monkeys ) received the vehicle at an application volume of 2.5 mL / kg body weight in the same manner and another control group ( 4 female monkeys ) received 0.9 % ( w / v ) sodium chloride solution at an application volume of 2.5 mL / kg body weight in the same manner .

[ "In", "addition", ",", "one", "control", "group", "(", "4", "female", "monkeys", ")", "received", "the", "vehicle", "at", "an", "application", "volume", "of", "2.5", "mL", "/", "kg", "body", "weight", "in", "the", "same", "manner", "and", "another", "control", "group", "(", "4", "female", "monkeys", ")", "received", "0.9", "%", "(", "w", "/", "v", ")", "sodium", "chloride", "solution", "at", "an", "application", "volume", "of", "2.5", "mL", "/", "kg", "body", "weight", "in", "the", "same", "manner", "." ]

[ "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Due to the cessation of development of COMPOUND_XXX , only selected target organs in female animals at the end of the treatment period were examined histologically .

[ "Due", "to", "the", "cessation", "of", "development", "of", "COMPOUND_XXX", ",", "only", "selected", "target", "organs", "in", "female", "animals", "at", "the", "end", "of", "the", "treatment", "period", "were", "examined", "histologically", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Following a 4 - week recovery period , thyroid , thymic , and testicular changes were considered to be fully reversible whereas lymph node and epididymal changes were partially reversible .

[ "Following", "a", "4", "-", "week", "recovery", "period", ",", "thyroid", ",", "thymic", ",", "and", "testicular", "changes", "were", "considered", "to", "be", "fully", "reversible", "whereas", "lymph", "node", "and", "epididymal", "changes", "were", "partially", "reversible", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

At gross pathology four 40 mg / kg / d males showed minimal to mild , multifocal beige discoloration of the kidney .

[ "At", "gross", "pathology", "four", "40", "mg", "/", "kg", "/", "d", "males", "showed", "minimal", "to", "mild", ",", "multifocal", "beige", "discoloration", "of", "the", "kidney", "." ]

[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "B-SEX", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN" ]

[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 5, 0, 0, 0, 0, 0, 8, 9, 9, 0, 0, 10, 11 ]

NO_PRETOX_REL

At the genomic level , COMPOUND_XXX did not induce any noteworthy transcriptional changes in heart or skeletal muscle at 40 or 80 mg / kg after treatment for 3 or 28 days .

[ "At", "the", "genomic", "level", ",", "COMPOUND_XXX", "did", "not", "induce", "any", "noteworthy", "transcriptional", "changes", "in", "heart", "or", "skeletal", "muscle", "at", "40", "or", "80", "mg", "/", "kg", "after", "treatment", "for", "3", "or", "28", "days", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

At the end of recovery , high dose ( 30 mg / kg ) recovery animals had the same incidence and degree of cytoplasmic vacuolation of interstitital cells as the main kill animals of this dose level .

[ "At", "the", "end", "of", "recovery", ",", "high", "dose", "(", "30", "mg", "/", "kg", ")", "recovery", "animals", "had", "the", "same", "incidence", "and", "degree", "of", "cytoplasmic", "vacuolation", "of", "interstitital", "cells", "as", "the", "main", "kill", "animals", "of", "this", "dose", "level", "." ]

[ "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The determination of a maximum tolerated dose ( MTD ) in this study is mainly based on the finding that body weight gain and survival of the monkeys were not affected at all three dose levels .

[ "The", "determination", "of", "a", "maximum", "tolerated", "dose", "(", "MTD", ")", "in", "this", "study", "is", "mainly", "based", "on", "the", "finding", "that", "body", "weight", "gain", "and", "survival", "of", "the", "monkeys", "were", "not", "affected", "at", "all", "three", "dose", "levels", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Individual animals presented with slight to marked decreases in white blood cell counts .

[ "Individual", "animals", "presented", "with", "slight", "to", "marked", "decreases", "in", "white", "blood", "cell", "counts", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 1, 0, 2, 6, 6, 6, 0 ]

PRETOX_REL

Diarrhea and missing defecation were incidental findings deemed unrelated to treatment with the test substance .

[ "Diarrhea", "and", "missing", "defecation", "were", "incidental", "findings", "deemed", "unrelated", "to", "treatment", "with", "the", "test", "substance", "." ]

[ "B-FINDING", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 8, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Thereafter the mean body weight gain of males was comparable between the treated and the control group .

[ "Thereafter", "the", "mean", "body", "weight", "gain", "of", "males", "was", "comparable", "between", "the", "treated", "and", "the", "control", "group", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]

NO_PRETOX_REL

Food consumption , ophthalmology , clinical chemistry and organ weight investigations did not reveal any treatment - related findings .

[ "Food", "consumption", ",", "ophthalmology", ",", "clinical", "chemistry", "and", "organ", "weight", "investigations", "did", "not", "reveal", "any", "treatment", "-", "related", "findings", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

At the terminal necropsy , organ weight changes included increased heart weights in males at doses : ; : : : 15 mg / kg / day and in females at 50 mg / kg / day ; decreased spleen weights in males at doses : ; : : : 15 mg!kg / day ; and at 50 mg / kg / day , increased adrenal weights in both sexes ; increased liver and thyroid weights in males ; increased ovary weights and decreased pituitary weights in females and decreased testis weights .

[ "At", "the", "terminal", "necropsy", ",", "organ", "weight", "changes", "included", "increased", "heart", "weights", "in", "males", "at", "doses", ":", ";", ":", ":", ":", "15", "mg", "/", "kg", "/", "day", "and", "in", "females", "at", "50", "mg", "/", "kg", "/", "day", ";", "decreased", "spleen", "weights", "in", "males", "at", "doses", ":", ";", ":", ":", ":", "15", "mg!kg", "/", "day", ";", "and", "at", "50", "mg", "/", "kg", "/", "day", ",", "increased", "adrenal", "weights", "in", "both", "sexes", ";", "increased", "liver", "and", "thyroid", "weights", "in", "males", ";", "increased", "ovary", "weights", "and", "decreased", "pituitary", "weights", "in", "females", "and", "decreased", "testis", "weights", "." ]

[ "O", "O", "O", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "I-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O" ]

[ 0, 0, 0, 0, 0, 10, 2, 1, 0, 1, 10, 2, 0, 5, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 1, 10, 2, 0, 5, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 1, 10, 2, 0, 5, 7, 0, 1, 10, 0, 10, 2, 0, 5, 0, 1, 10, 2, 0, 1, 10, 2, 0, 5, 0, 1, 10, 2, 0 ]

PRETOX_REL

CONCLUSION In conclusion , the administration of COMPOUND_XXX by daily oral gavage for 3 or 10 days at dose levels of 0 , 50 mg / kg / day and 200 mg / kg / day resulted in clinical signs of dehydration and fur staining red , adverse reductions in body weight gain with associated reduced food consumption , minor hematology ( prolonged PT ) , biochemical ( increased BUN ) , significant urinalysis changes ( increased urinary protein and occult blood , glycosuria and polyuria ) , with associated macroscopic ( pale discolouration in medulla or corticomedullary junction ) and microscopic changes ( tubular degeneration / regeneration in the outer medulla ) in the kidney of rats treated with 200 mg / kg / day COMPOUND_XXX .

[ "CONCLUSION", "In", "conclusion", ",", "the", "administration", "of", "COMPOUND_XXX", "by", "daily", "oral", "gavage", "for", "3", "or", "10", "days", "at", "dose", "levels", "of", "0", ",", "50", "mg", "/", "kg", "/", "day", "and", "200", "mg", "/", "kg", "/", "day", "resulted", "in", "clinical", "signs", "of", "dehydration", "and", "fur", "staining", "red", ",", "adverse", "reductions", "in", "body", "weight", "gain", "with", "associated", "reduced", "food", "consumption", ",", "minor", "hematology", "(", "prolonged", "PT", ")", ",", "biochemical", "(", "increased", "BUN", ")", ",", "significant", "urinalysis", "changes", "(", "increased", "urinary", "protein", "and", "occult", "blood", ",", "glycosuria", "and", "polyuria", ")", ",", "with", "associated", "macroscopic", "(", "pale", "discolouration", "in", "medulla", "or", "corticomedullary", "junction", ")", "and", "microscopic", "changes", "(", "tubular", "degeneration", "/", "regeneration", "in", "the", "outer", "medulla", ")", "in", "the", "kidney", "of", "rats", "treated", "with", "200", "mg", "/", "kg", "/", "day", "COMPOUND_XXX", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-FINDING", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-SPECIMEN", "O", "O", "O", "B-SPECIMEN", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 8, 0, 8, 9, 9, 0, 0, 1, 0, 2, 6, 6, 0, 0, 1, 2, 6, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 1, 2, 0, 0, 0, 2, 1, 0, 1, 2, 6, 0, 2, 6, 0, 8, 0, 8, 0, 0, 0, 0, 0, 0, 8, 9, 0, 10, 0, 10, 11, 0, 0, 0, 0, 0, 8, 9, 9, 9, 0, 0, 0, 10, 0, 0, 0, 10, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0 ]

NO_PRETOX_REL

An additional group of rats ( 10 / sex ) received vehicle ( Purified Water , USP ) at an equivalent dosing volume ( 10 mL / kg ) and served as a control .

[ "An", "additional", "group", "of", "rats", "(", "10", "/", "sex", ")", "received", "vehicle", "(", "Purified", "Water", ",", "USP", ")", "at", "an", "equivalent", "dosing", "volume", "(", "10", "mL", "/", "kg", ")", "and", "served", "as", "a", "control", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The high dose of 375 μmol Gd / kg bw .

[ "The", "high", "dose", "of", "375", "μmol", "Gd", "/", "kg", "bw", "." ]

[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 15, 16, 0, 3, 4, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

One animal dosed at 80 mg / kg bw .

[ "One", "animal", "dosed", "at", "80", "mg", "/", "kg", "bw", "." ]

[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

Toxicokinetic data indicate a moderately fast absorption of the test compound after intragastric administration , a minor to moderate accumulation potential of the drug after daily administration and a higher systemic exposure ( AUC ( 0 - t last ) ) in female compared to male Beagle dogs .

[ "Toxicokinetic", "data", "indicate", "a", "moderately", "fast", "absorption", "of", "the", "test", "compound", "after", "intragastric", "administration", ",", "a", "minor", "to", "moderate", "accumulation", "potential", "of", "the", "drug", "after", "daily", "administration", "and", "a", "higher", "systemic", "exposure", "(", "AUC", "(", "0", "-", "t", "last", ")", ")", "in", "female", "compared", "to", "male", "Beagle", "dogs", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

In the current study , in - life and terminal data collection included , clinical observations , body weight , food consumption , clinical pathology , full necropsy , organ weight analysis and comprehensive histopathology of selected tissues .

[ "In", "the", "current", "study", ",", "in", "-", "life", "and", "terminal", "data", "collection", "included", ",", "clinical", "observations", ",", "body", "weight", ",", "food", "consumption", ",", "clinical", "pathology", ",", "full", "necropsy", ",", "organ", "weight", "analysis", "and", "comprehensive", "histopathology", "of", "selected", "tissues", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

COMPOUND_XXX has shown a predictable cholinomimetic profile in the one year chronic toxicity studies in the rat .

[ "COMPOUND_XXX", "has", "shown", "a", "predictable", "cholinomimetic", "profile", "in", "the", "one", "year", "chronic", "toxicity", "studies", "in", "the", "rat", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

A consequence of the hyperostosis is the increased hemopoiesis in the spleen in the high dose group .

[ "A", "consequence", "of", "the", "hyperostosis", "is", "the", "increased", "hemopoiesis", "in", "the", "spleen", "in", "the", "high", "dose", "group", "." ]

[ "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O" ]

[ 0, 0, 0, 0, 8, 0, 0, 8, 9, 0, 0, 10, 0, 0, 12, 13, 13, 0 ]

PRETOX_REL

Local reactions were found in both control and compound - treated group indicating mechanical irritation .

[ "Local", "reactions", "were", "found", "in", "both", "control", "and", "compound", "-", "treated", "group", "indicating", "mechanical", "irritation", "." ]

[ "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-FINDING", "I-FINDING", "O" ]

[ 8, 9, 0, 0, 0, 0, 12, 13, 13, 13, 13, 13, 0, 8, 9, 0 ]

PRETOX_REL

Clinical chemistry alterations noted just prior to sacrifice included moderate hyponatremia , marked hypochloridemia , hyperproteinemia , hypoglycemia , increased serum triglyceride concentration and moderate azotemia / uremia .

[ "Clinical", "chemistry", "alterations", "noted", "just", "prior", "to", "sacrifice", "included", "moderate", "hyponatremia", ",", "marked", "hypochloridemia", ",", "hyperproteinemia", ",", "hypoglycemia", ",", "increased", "serum", "triglyceride", "concentration", "and", "moderate", "azotemia", "/", "uremia", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-FINDING", "O", "B-FINDING", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 8, 0, 8, 0, 8, 0, 1, 10, 2, 6, 0, 0, 8, 0, 8, 0 ]

PRETOX_REL

Food Consumption : Slight reductions in food consumption were observed in females given 600 mg / kg / day .

[ "Food", "Consumption", ":", "Slight", "reductions", "in", "food", "consumption", "were", "observed", "in", "females", "given", "600", "mg", "/", "kg", "/", "day", "." ]

[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 1, 0, 2, 6, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

The deaths were not considered treatment - related .

[ "The", "deaths", "were", "not", "considered", "treatment", "-", "related", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Likely due to effects of COMPOUND_XXX on fast renewal cells division cycle by Met receptor tyrosine kinase inhibition and associated changes : - disorganisations of the intestinal epithelium and / or the increase in the apoptotic bodies number were noted in both sexes at 40 mg / kg only with a severity and incidence more marked in dosed - females .

[ "Likely", "due", "to", "effects", "of", "COMPOUND_XXX", "on", "fast", "renewal", "cells", "division", "cycle", "by", "Met", "receptor", "tyrosine", "kinase", "inhibition", "and", "associated", "changes", ":", "-", "disorganisations", "of", "the", "intestinal", "epithelium", "and", "/", "or", "the", "increase", "in", "the", "apoptotic", "bodies", "number", "were", "noted", "in", "both", "sexes", "at", "40", "mg", "/", "kg", "only", "with", "a", "severity", "and", "incidence", "more", "marked", "in", "dosed", "-", "females", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 10, 11, 0, 0, 0, 0, 1, 0, 0, 8, 9, 0, 0, 0, 0, 5, 7, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The compound could be injected by the intravenous route even in group IV for more than 4 weeks .

[ "The", "compound", "could", "be", "injected", "by", "the", "intravenous", "route", "even", "in", "group", "IV", "for", "more", "than", "4", "weeks", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Several animals also showed slight skin erythema at the sites covered by FixomuiiR , probably due to the daily removal procedures .

[ "Several", "animals", "also", "showed", "slight", "skin", "erythema", "at", "the", "sites", "covered", "by", "FixomuiiR", ",", "probably", "due", "to", "the", "daily", "removal", "procedures", "." ]

[ "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The relative exposure of COMPOUND_XXX to Ganciclovir was only 1 - 2 % and the relative peak concentrations were only 6 - 13 % .

[ "The", "relative", "exposure", "of", "COMPOUND_XXX", "to", "Ganciclovir", "was", "only", "1", "-", "2", "%", "and", "the", "relative", "peak", "concentrations", "were", "only", "6", "-", "13", "%", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

All test article - treated animals exhibited measurable concentrations of COMPOUND_XXX .

[ "All", "test", "article", "-", "treated", "animals", "exhibited", "measurable", "concentrations", "of", "COMPOUND_XXX", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

In - life effects included fecal changes ( soft , reduced and absent feces ) in both sexes at 150 ~ 100 mg / kg / day with increased incidence in the females .

[ "In", "-", "life", "effects", "included", "fecal", "changes", "(", "soft", ",", "reduced", "and", "absent", "feces", ")", "in", "both", "sexes", "at", "150", "~", "100", "mg", "/", "kg", "/", "day", "with", "increased", "incidence", "in", "the", "females", "." ]

[ "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "B-SPECIMEN", "O", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-SEX", "O" ]

[ 0, 0, 0, 0, 0, 8, 9, 0, 8, 0, 8, 0, 8, 10, 0, 0, 5, 7, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 5, 0 ]

NO_PRETOX_REL

The later is an indirect consequence of the inhibition of PDGFR which also involves insuline - like - growth factor 1 ( IGF1 ) / phosphoinositid -3-kinase ( Pi3K ) pathway .

[ "The", "later", "is", "an", "indirect", "consequence", "of", "the", "inhibition", "of", "PDGFR", "which", "also", "involves", "insuline", "-", "like", "-", "growth", "factor", "1", "(", "IGF1", ")", "/", "phosphoinositid", "-3-kinase", "(", "Pi3K", ")", "pathway", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Microscopic examinations were performed on gross lesions and protocol - specified set of tissues from all animals .

[ "Microscopic", "examinations", "were", "performed", "on", "gross", "lesions", "and", "protocol", "-", "specified", "set", "of", "tissues", "from", "all", "animals", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

This effect was reversible No compound - related effects were noted in water consumption and in ophthalmoscopical examination .

[ "This", "effect", "was", "reversible", "No", "compound", "-", "related", "effects", "were", "noted", "in", "water", "consumption", "and", "in", "ophthalmoscopical", "examination", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Findings observed in animals exposed to COMPOUND_XXX at a daily dose of 10 umol / kg bw .

[ "Findings", "observed", "in", "animals", "exposed", "to", "COMPOUND_XXX", "at", "a", "daily", "dose", "of", "10", "umol", "/", "kg", "bw", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

Systemic exposure decreased over proportionally with decreasing dose .

[ "Systemic", "exposure", "decreased", "over", "proportionally", "with", "decreasing", "dose", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

Alterations of laboratory parameters are considered to be secondary effects due to inflammatory processes in the lung .

[ "Alterations", "of", "laboratory", "parameters", "are", "considered", "to", "be", "secondary", "effects", "due", "to", "inflammatory", "processes", "in", "the", "lung", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 0 ]

NO_PRETOX_REL

Histological examination performed on the ovaries , testes and epididymes ( with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure ) of the animals of the 225 mg / kg / group and the control group did not evidence any toxicological pathomorphological lesions .

[ "Histological", "examination", "performed", "on", "the", "ovaries", ",", "testes", "and", "epididymes", "(", "with", "special", "emphasis", "on", "stages", "of", "spermatogenesis", "and", "histopathology", "of", "interstitial", "testicular", "cell", "structure", ")", "of", "the", "animals", "of", "the", "225", "mg", "/", "kg", "/", "group", "and", "the", "control", "group", "did", "not", "evidence", "any", "toxicological", "pathomorphological", "lesions", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

With the exception of several animals of the low dose group , all dogs were exposed to the test compound over the entire 24 h dosing interval .

[ "With", "the", "exception", "of", "several", "animals", "of", "the", "low", "dose", "group", ",", "all", "dogs", "were", "exposed", "to", "the", "test", "compound", "over", "the", "entire", "24", "h", "dosing", "interval", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

In addition , heart and skeletal muscle were sampled for gene expression analysis and determination of COMPOUND_XXX tissue concentrations ( about 3 hours after 28th dose ) .

[ "In", "addition", ",", "heart", "and", "skeletal", "muscle", "were", "sampled", "for", "gene", "expression", "analysis", "and", "determination", "of", "COMPOUND_XXX", "tissue", "concentrations", "(", "about", "3", "hours", "after", "28th", "dose", ")", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Signs of recovery could be detected in some animals .

[ "Signs", "of", "recovery", "could", "be", "detected", "in", "some", "animals", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Post-mortem investigations included organ weights , macroscopic and microscopic examinations .

[ "Post-mortem", "investigations", "included", "organ", "weights", ",", "macroscopic", "and", "microscopic", "examinations", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Due to the distinct pharmacological activity of the compound even at the low dose , a NOEL was not identified .

[ "Due", "to", "the", "distinct", "pharmacological", "activity", "of", "the", "compound", "even", "at", "the", "low", "dose", ",", "a", "NOEL", "was", "not", "identified", "." ]

[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0, 0 ]

PRETOX_REL

One high - dose female ( no. 4501 ) was sacrificed due to poor condition on day 13 .

[ "One", "high", "-", "dose", "female", "(", "no.", "4501", ")", "was", "sacrificed", "due", "to", "poor", "condition", "on", "day", "13", "." ]

[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O" ]

[ 0, 15, 16, 16, 5, 0, 0, 0, 0, 0, 8, 0, 0, 8, 9, 0, 0, 0, 0 ]

NO_PRETOX_REL

After -4 weeks , the high dose was reduced from 20 mg / kg / day to 10 mg / kg / day .

[ "After", "-4", "weeks", ",", "the", "high", "dose", "was", "reduced", "from", "20", "mg", "/", "kg", "/", "day", "to", "10", "mg", "/", "kg", "/", "day", "." ]

[ "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]

[ 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 3, 4, 4, 4, 4, 4, 0 ]

PRETOX_REL

Anemia and atrophy in the bone marrow and lymphatic organs were considered to be associated with the pharmacological action of COMPOUND_XXX .

[ "Anemia", "and", "atrophy", "in", "the", "bone", "marrow", "and", "lymphatic", "organs", "were", "considered", "to", "be", "associated", "with", "the", "pharmacological", "action", "of", "COMPOUND_XXX", "." ]

[ "B-FINDING", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 8, 0, 8, 0, 0, 10, 11, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

At 1.2 mg / kg , the AUC and Cmax were 220 and 193 ng · h / mL and 185 and 169 ng / mL for males and females , respectively ( day 85 ) .

[ "At", "1.2", "mg", "/", "kg", ",", "the", "AUC", "and", "Cmax", "were", "220", "and", "193", "ng", "·", "h", "/", "mL", "and", "185", "and", "169", "ng", "/", "mL", "for", "males", "and", "females", ",", "respectively", "(", "day", "85", ")", "." ]

[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]

[ 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]