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
NO_PRETOX_REL	The purpose of this study was to establish the toxicologic effects of COMPOUND_XXX , a histone deacetylase inhibitor , when administered intravenously to rats for 13 weeks using a once weekly dosing schedule .	[ "The", "purpose", "of", "this", "study", "was", "to", "establish", "the", "toxicologic", "effects", "of", "COMPOUND_XXX", ",", "a", "histone", "deacetylase", "inhibitor", ",", "when", "administered", "intravenously", "to", "rats", "for", "13", "weeks", "using", "a", "once", "weekly", "dosing", "schedule", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "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 ]
PRETOX_REL	vomit and hypersalivation in males and females treated at 75 mg / kg / day , .	[ "vomit", "and", "hypersalivation", "in", "males", "and", "females", "treated", "at", "75", "mg", "/", "kg", "/", "day", ",", "." ]	[ "B-FINDING", "O", "B-FINDING", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]	[ 8, 0, 8, 0, 5, 7, 7, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0 ]
PRETOX_REL	Sporadic food left was observed at 25 mg / kg and higher .	[ "Sporadic", "food", "left", "was", "observed", "at", "25", "mg", "/", "kg", "and", "higher", "." ]	[ "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O" ]	[ 8, 9, 9, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0 ]
NO_PRETOX_REL	Concerning the water intake , there were no descriptions of unusual findings in water intake in the observation records .	[ "Concerning", "the", "water", "intake", ",", "there", "were", "no", "descriptions", "of", "unusual", "findings", "in", "water", "intake", "in", "the", "observation", "records", "." ]	[ "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	Three groups will be treated with one formulation at three different concentrations ( 0 % , 10 % and 20 % ) .	[ "Three", "groups", "will", "be", "treated", "with", "one", "formulation", "at", "three", "different", "concentrations", "(", "0", "%", ",", "10", "%", "and", "20", "%", ")", "." ]	[ "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 ]
PRETOX_REL	Rales was occasionally observed in the 600 and 2000 mgikgíday groups one hour following dosing .	[ "Rales", "was", "occasionally", "observed", "in", "the", "600", "and", "2000", "mgikgíday", "groups", "one", "hour", "following", "dosing", "." ]	[ "B-FINDING", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O" ]	[ 8, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In animals with renal changes , the bone changes were complicated by secondary increases in bone resorption of tibia and alveolar bones .	[ "In", "animals", "with", "renal", "changes", ",", "the", "bone", "changes", "were", "complicated", "by", "secondary", "increases", "in", "bone", "resorption", "of", "tibia", "and", "alveolar", "bones", "." ]	[ "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "B-FINDING", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-FINDING", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 8, 9, 0, 0, 10, 8, 0, 0, 0, 0, 1, 0, 10, 8, 0, 10, 0, 10, 11, 0 ]
PRETOX_REL	Statistically significant drug - related decrease in body weight gains were detected in the high dose males ( 15 % ) and low ( 10 % ) , mid ( 10 % ) and high dose ( 27 % ) females .	[ "Statistically", "significant", "drug", "-", "related", "decrease", "in", "body", "weight", "gains", "were", "detected", "in", "the", "high", "dose", "males", "(", "15", "%", ")", "and", "low", "(", "10", "%", ")", ",", "mid", "(", "10", "%", ")", "and", "high", "dose", "(", "27", "%", ")", "females", "." ]	[ "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 1, 0, 2, 6, 6, 0, 0, 0, 0, 15, 16, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The present data set gives no indication of gender - specific differences in pharmacokinetics of COMPOUND_XXX in minipigs .	[ "The", "present", "data", "set", "gives", "no", "indication", "of", "gender", "-", "specific", "differences", "in", "pharmacokinetics", "of", "COMPOUND_XXX", "in", "minipigs", "." ]	[ "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	The spermatogenesis was markedly impaired .	[ "The", "spermatogenesis", "was", "markedly", "impaired", "." ]	[ "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 0, 8, 9, 9, 9, 0 ]
PRETOX_REL	Adrenal cortical alterations increased with treatment duration and included vacuolation , hypertrophy , single cell necrosis , hemorrhage / congestion and inflammatory cell infiltration and after the recovery period pigment deposition .	[ "Adrenal", "cortical", "alterations", "increased", "with", "treatment", "duration", "and", "included", "vacuolation", ",", "hypertrophy", ",", "single", "cell", "necrosis", ",", "hemorrhage", "/", "congestion", "and", "inflammatory", "cell", "infiltration", "and", "after", "the", "recovery", "period", "pigment", "deposition", "." ]	[ "B-SPECIMEN", "I-SPECIMEN", "B-FINDING", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O" ]	[ 10, 11, 8, 1, 0, 0, 0, 0, 0, 8, 0, 8, 0, 8, 9, 9, 0, 8, 9, 9, 0, 8, 9, 9, 0, 0, 0, 0, 0, 8, 9, 0 ]
PRETOX_REL	In conclusion , treatment with COMPOUND_XXX caused a notably high early mortality at a dose of 600 mg / kg / day , a dose - related decrease in serum glucose , and minimal to mild axonal degeneration in sciatic ( peripheral ) nerves of rats treated with 100 , 300 , or 600 mg / kg / day of COMPOUND_XXX .	[ "In", "conclusion", ",", "treatment", "with", "COMPOUND_XXX", "caused", "a", "notably", "high", "early", "mortality", "at", "a", "dose", "of", "600", "mg", "/", "kg", "/", "day", ",", "a", "dose", "-", "related", "decrease", "in", "serum", "glucose", ",", "and", "minimal", "to", "mild", "axonal", "degeneration", "in", "sciatic", "(", "peripheral", ")", "nerves", "of", "rats", "treated", "with", "100", ",", "300", ",", "or", "600", "mg", "/", "kg", "/", "day", "of", "COMPOUND_XXX", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "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", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 1, 0, 2, 6, 0, 0, 1, 14, 14, 8, 9, 0, 10, 11, 11, 11, 11, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0 ]
NO_PRETOX_REL	Electron microscopic evaluation of heart tissue from selected animals treated with COMPOUND_XXX at 80 mg / kg for 28 days generally showed the same ultra-morphology of all cellular organelles as the corresponding control animals .	[ "Electron", "microscopic", "evaluation", "of", "heart", "tissue", "from", "selected", "animals", "treated", "with", "COMPOUND_XXX", "at", "80", "mg", "/", "kg", "for", "28", "days", "generally", "showed", "the", "same", "ultra-morphology", "of", "all", "cellular", "organelles", "as", "the", "corresponding", "control", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "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" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The dogs in all test article - treated groups were exposed to COMPOUND_XXX .	[ "The", "dogs", "in", "all", "test", "article", "-", "treated", "groups", "were", "exposed", "to", "COMPOUND_XXX", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0 ]
PRETOX_REL	Electron microscopy revealed the occurrence of myeloid bodies in endothelial cells of heart and skeletal muscle which was distinct to striking and numerous after treatment with COMPOUND_XXX at 180 mg / kg / day .	[ "Electron", "microscopy", "revealed", "the", "occurrence", "of", "myeloid", "bodies", "in", "endothelial", "cells", "of", "heart", "and", "skeletal", "muscle", "which", "was", "distinct", "to", "striking", "and", "numerous", "after", "treatment", "with", "COMPOUND_XXX", "at", "180", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "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, 8, 9, 0, 10, 11, 0, 10, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	Various forms of Plasmodium sp , present in rare to occasional numbers , were identified microscopically in Wright 's stained blood films in animals of both sexes at doses ~ 30 mglkg / day and in two low - dose males .	[ "Various", "forms", "of", "Plasmodium", "sp", ",", "present", "in", "rare", "to", "occasional", "numbers", ",", "were", "identified", "microscopically", "in", "Wright", "'s", "stained", "blood", "films", "in", "animals", "of", "both", "sexes", "at", "doses", "~", "30", "mglkg", "/", "day", "and", "in", "two", "low", "-", "dose", "males", "." ]	[ "O", "O", "O", "O", "O", "O", "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", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "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, 3, 4, 4, 4, 0, 0, 0, 15, 16, 16, 0, 0 ]
NO_PRETOX_REL	The exposure after approximately 11 and 25 weeks of treatment on a 3 doses / week regime was similar but was higher than exposure on Day 1 .	[ "The", "exposure", "after", "approximately", "11", "and", "25", "weeks", "of", "treatment", "on", "a", "3", "doses", "/", "week", "regime", "was", "similar", "but", "was", "higher", "than", "exposure", "on", "Day", "1", "." ]	[ "O", "O", "O", "O", "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 ]
PRETOX_REL	The principal test article - related microscopic findings consisted of thyroid changes ( ~ 0.06 mg / kg / day ) , depletion of lymphoid tissue ( ~ 0.2 mg / kg / day ) , thymic atrophy ( 0.6 mg / kg / day ) , decreased bone marrow hematopoiesis ( 0.6 mg / kg / day ) , and intracellular pigment deposition at various sites ( ~ 0.2 mg / kg / day ) .	[ "The", "principal", "test", "article", "-", "related", "microscopic", "findings", "consisted", "of", "thyroid", "changes", "(", "~", "0.06", "mg", "/", "kg", "/", "day", ")", ",", "depletion", "of", "lymphoid", "tissue", "(", "~", "0.2", "mg", "/", "kg", "/", "day", ")", ",", "thymic", "atrophy", "(", "0.6", "mg", "/", "kg", "/", "day", ")", ",", "decreased", "bone", "marrow", "hematopoiesis", "(", "0.6", "mg", "/", "kg", "/", "day", ")", ",", "and", "intracellular", "pigment", "deposition", "at", "various", "sites", "(", "~", "0.2", "mg", "/", "kg", "/", "day", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SPECIMEN", "B-FINDING", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-FINDING", "I-FINDING", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "I-SPECIMEN", "B-FINDING", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "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, 10, 8, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 8, 0, 10, 11, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 8, 9, 0, 3, 4, 4, 4, 4, 4, 0, 0, 1, 10, 11, 8, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 8, 9, 9, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0 ]
PRETOX_REL	Slight reductions in body - weight gain and food consumption were observed in males and females given 225 and 500 mgikg / day of NS and in females given 500 mg / kHday of OS .	[ "Slight", "reductions", "in", "body", "-", "weight", "gain", "and", "food", "consumption", "were", "observed", "in", "males", "and", "females", "given", "225", "and", "500", "mgikg", "/", "day", "of", "NS", "and", "in", "females", "given", "500", "mg", "/", "kHday", "of", "OS", "." ]	[ "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O" ]	[ 0, 1, 0, 2, 6, 6, 6, 0, 2, 6, 0, 0, 0, 5, 7, 7, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 0 ]
PRETOX_REL	At the high dose these lung findings escalated to diffuse foam cell aggregation associated with acute / mixed inflammation and hyperplasia of alveolar type II pneumocytes .	[ "At", "the", "high", "dose", "these", "lung", "findings", "escalated", "to", "diffuse", "foam", "cell", "aggregation", "associated", "with", "acute", "/", "mixed", "inflammation", "and", "hyperplasia", "of", "alveolar", "type", "II", "pneumocytes", "." ]	[ "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-SPECIMEN", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 0, 0, 15, 16, 0, 10, 0, 0, 0, 0, 8, 9, 9, 0, 0, 8, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 0 ]
PRETOX_REL	, 20 Due to a moribund condition animal H 062 / group \| had to be sacrificed prematurely at the end of week 13 of the study ( see also , a. Clinical observations " ) .	[ ",", "20", "Due", "to", "a", "moribund", "condition", "animal", "H", "062", "/", "group", "\|", "had", "to", "be", "sacrificed", "prematurely", "at", "the", "end", "of", "week", "13", "of", "the", "study", "(", "see", "also", ",", "a.", "Clinical", "observations", "\"", ")", "." ]	[ "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "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, 12, 13, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	One 30 mg / kg female showed a markedly increased GLDH value ( animal no. 36 ) .	[ "One", "30", "mg", "/", "kg", "female", "showed", "a", "markedly", "increased", "GLDH", "value", "(", "animal", "no.", "36", ")", "." ]	[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "B-SEX", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 3, 4, 4, 4, 5, 0, 0, 0, 1, 2, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Additionally , all group III ( 30/60 mg / kg ) - males showed a minimal infiltration with granulocytes .	[ "Additionally", ",", "all", "group", "III", "(", "30/60", "mg", "/", "kg", ")", "-", "males", "showed", "a", "minimal", "infiltration", "with", "granulocytes", "." ]	[ "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 0, 0, 0, 12, 13, 0, 3, 4, 4, 4, 0, 0, 5, 0, 0, 0, 8, 9, 9, 0 ]
PRETOX_REL	As can be seen from the table , feed intake was slightly reduced in group Ill - males in comparison to control animals whereas in females no changes were observed up to and including group III .	[ "As", "can", "be", "seen", "from", "the", "table", ",", "feed", "intake", "was", "slightly", "reduced", "in", "group", "Ill", "-", "males", "in", "comparison", "to", "control", "animals", "whereas", "in", "females", "no", "changes", "were", "observed", "up", "to", "and", "including", "group", "III", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-GROUP", "I-GROUP", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 2, 6, 0, 0, 1, 0, 12, 13, 0, 5, 0, 0, 0, 0, 0, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
PRETOX_REL	Increased serum TSH levels and increased relative kidney weights were observed in female rats .	[ "Increased", "serum", "TSH", "levels", "and", "increased", "relative", "kidney", "weights", "were", "observed", "in", "female", "rats", "." ]	[ "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "O" ]	[ 1, 2, 6, 6, 0, 1, 0, 10, 2, 0, 0, 0, 5, 0, 0 ]
NO_PRETOX_REL	The mechanisms of toxicity and surrogate markers were also evaluated .	[ "The", "mechanisms", "of", "toxicity", "and", "surrogate", "markers", "were", "also", "evaluated", "." ]	[ "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	In uterine samples mean concentrations of COMPOUND_XXX were about 1000 times higher than the highest serum concentrations measured ( TT 1 ) .	[ "In", "uterine", "samples", "mean", "concentrations", "of", "COMPOUND_XXX", "were", "about", "1000", "times", "higher", "than", "the", "highest", "serum", "concentrations", "measured", "(", "TT", "1", ")", "." ]	[ "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 ]
PRETOX_REL	In addition at the mid dose of 20 mg / kg COMPOUND_XXX per day and higher : Clinical examinations : - emaciation occurred in one male animal of the mid dose .	[ "In", "addition", "at", "the", "mid", "dose", "of", "20", "mg", "/", "kg", "COMPOUND_XXX", "per", "day", "and", "higher", ":", "Clinical", "examinations", ":", "-", "emaciation", "occurred", "in", "one", "male", "animal", "of", "the", "mid", "dose", "." ]	[ "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "B-SEX", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O" ]	[ 0, 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 0, 5, 0, 0, 0, 15, 16, 0 ]
NO_PRETOX_REL	Protocol - specified organs were weighed and tissues were collected , processed and microscopically examined for all animals .	[ "Protocol", "-", "specified", "organs", "were", "weighed", "and", "tissues", "were", "collected", ",", "processed", "and", "microscopically", "examined", "for", "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	The only histopathological finding related to COMPOUND_XXX treatment was minimal to slight segmental degeneration of the sciatic nerve in female rats , which was evident in at least one animal at all dose levels .	[ "The", "only", "histopathological", "finding", "related", "to", "COMPOUND_XXX", "treatment", "was", "minimal", "to", "slight", "segmental", "degeneration", "of", "the", "sciatic", "nerve", "in", "female", "rats", ",", "which", "was", "evident", "in", "at", "least", "one", "animal", "at", "all", "dose", "levels", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 10, 11, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 0 ]
NO_PRETOX_REL	Accumulations of granulocytes are absent .	[ "Accumulations", "of", "granulocytes", "are", "absent", "." ]	[ "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Transient local effects at the application site were limited to occasional erythema , mainly at the high dose during the first 9 weeks of the study and a slightly lower body weight gain was noted in treated males of all groups including Placebo Nail Lacquer and in females at 270 mg / kg compared with sham controls .	[ "Transient", "local", "effects", "at", "the", "application", "site", "were", "limited", "to", "occasional", "erythema", ",", "mainly", "at", "the", "high", "dose", "during", "the", "first", "9", "weeks", "of", "the", "study", "and", "a", "slightly", "lower", "body", "weight", "gain", "was", "noted", "in", "treated", "males", "of", "all", "groups", "including", "Placebo", "Nail", "Lacquer", "and", "in", "females", "at", "270", "mg", "/", "kg", "compared", "with", "sham", "controls", "." ]	[ "O", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-SEX", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 10, 11, 0, 0, 0, 0, 8, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 14, 2, 6, 6, 0, 0, 0, 0, 5, 0, 12, 13, 0, 0, 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	On Day I. peak plasma concentrations in males were 266 ± 340 ng / ml , 529 ± 224 ng / ml and 1007 ± 440 ng / ml for 5 , 15 and 60 mg / kg / day respectively .	[ "On", "Day", "I.", "peak", "plasma", "concentrations", "in", "males", "were", "266", "±", "340", "ng", "/", "ml", ",", "529", "±", "224", "ng", "/", "ml", "and", "1007", "±", "440", "ng", "/", "ml", "for", "5", ",", "15", "and", "60", "mg", "/", "kg", "/", "day", "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", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0 ]
NO_PRETOX_REL	After treatment for 2 or 4 weeks , exposure to COMPOUND_XXX or its metabolite COMPOUND_XXX doseproportionally increased from 120 to 180 mg / kg / day while for an under - proportional increased exposure was observed from 5 to 15 mg / kg / day .	[ "After", "treatment", "for", "2", "or", "4", "weeks", ",", "exposure", "to", "COMPOUND_XXX", "or", "its", "metabolite", "COMPOUND_XXX", "doseproportionally", "increased", "from", "120", "to", "180", "mg", "/", "kg", "/", "day", "while", "for", "an", "under", "-", "proportional", "increased", "exposure", "was", "observed", "from", "5", "to", "15", "mg", "/", "kg", "/", "day", "." ]	[ "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", "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", "O" ]	[ 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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0 ]
PRETOX_REL	The lesion was characterized by a minimal or slight perivascular edema of larger arteries located in the proximal parts of the papillary muscle .	[ "The", "lesion", "was", "characterized", "by", "a", "minimal", "or", "slight", "perivascular", "edema", "of", "larger", "arteries", "located", "in", "the", "proximal", "parts", "of", "the", "papillary", "muscle", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 10, 11, 0 ]
PRETOX_REL	Adverse treatment - related effects were limited to slight , reversible degenerative changes in the sciatic nerve of female rats at all dose levels .	[ "Adverse", "treatment", "-", "related", "effects", "were", "limited", "to", "slight", ",", "reversible", "degenerative", "changes", "in", "the", "sciatic", "nerve", "of", "female", "rats", "at", "all", "dose", "levels", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 11, 0, 5, 0, 0, 3, 4, 4, 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 .	[ "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", "." ]	[ "O", "O", "O", "O", "O", "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 ]
NO_PRETOX_REL	There were no clinical signs of toxicity .	[ "There", "were", "no", "clinical", "signs", "of", "toxicity", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No clinical signs were observed .	[ "No", "clinical", "signs", "were", "observed", "." ]	[ "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The purpose of this study was to compare the toxicity and toxicokinetic profile of COMPOUND_XXX produced by a new route of chemical synthesis with that produced by the old route of synthesis .	[ "The", "purpose", "of", "this", "study", "was", "to", "compare", "the", "toxicity", "and", "toxicokinetic", "profile", "of", "COMPOUND_XXX", "produced", "by", "a", "new", "route", "of", "chemical", "synthesis", "with", "that", "produced", "by", "the", "old", "route", "of", "synthesis", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "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 ]
PRETOX_REL	With the exception of dermal lesions observed at the site of test article administration , no gross pathology findings were considered to be test article related .	[ "With", "the", "exception", "of", "dermal", "lesions", "observed", "at", "the", "site", "of", "test", "article", "administration", ",", "no", "gross", "pathology", "findings", "were", "considered", "to", "be", "test", "article", "related", "." ]	[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "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, 8, 9, 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 treatment period was followed by a four - week recovery period to determine the persistence or reversibility of any treatment - related effects .	[ "The", "treatment", "period", "was", "followed", "by", "a", "four", "-", "week", "recovery", "period", "to", "determine", "the", "persistence", "or", "reversibility", "of", "any", "treatment", "-", "related", "effects", "." ]	[ "O", "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 ]
PRETOX_REL	Anemia and slight increases in AST and ALT , indicative for hepatocellular damage , were further findings .	[ "Anemia", "and", "slight", "increases", "in", "AST", "and", "ALT", ",", "indicative", "for", "hepatocellular", "damage", ",", "were", "further", "findings", "." ]	[ "B-FINDING", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O" ]	[ 8, 0, 0, 1, 0, 2, 0, 2, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No relevant body and organ weight changes were found in females .	[ "No", "relevant", "body", "and", "organ", "weight", "changes", "were", "found", "in", "females", "." ]	[ "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	All changes were reversible on withdrawal of treatment .	[ "All", "changes", "were", "reversible", "on", "withdrawal", "of", "treatment", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Drug - related effects on food consumption were noted in Group · V animals , an approximate 10 - 15 % decrease was noted .	[ "Drug", "-", "related", "effects", "on", "food", "consumption", "were", "noted", "in", "Group", "·", "V", "animals", ",", "an", "approximate", "10", "-", "15", "%", "decrease", "was", "noted", "." ]	[ "O", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 2, 6, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0 ]
NO_PRETOX_REL	Clinical pathology evaluations ( hematology including coagulation , clinical chemistry and urinalysis ) were conducted on all animals during pretest and week 4 and at the end of the recovery period .	[ "Clinical", "pathology", "evaluations", "(", "hematology", "including", "coagulation", ",", "clinical", "chemistry", "and", "urinalysis", ")", "were", "conducted", "on", "all", "animals", "during", "pretest", "and", "week", "4", "and", "at", "the", "end", "of", "the", "recovery", "period", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "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	Complete coverage of the administration area with the test or reference item generally persisted for 1 to 5 days .	[ "Complete", "coverage", "of", "the", "administration", "area", "with", "the", "test", "or", "reference", "item", "generally", "persisted", "for", "1", "to", "5", "days", "." ]	[ "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 and clinical chemistry were performed during the last week of the study .	[ "Hematology", "and", "clinical", "chemistry", "were", "performed", "during", "the", "last", "week", "of", "the", "study", "." ]	[ "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	On Week 52 .	[ "On", "Week", "52", "." ]	[ "O", "O", "O", "O" ]	[ 0, 0, 0, 0 ]
NO_PRETOX_REL	This finding was no longer present at the end of recovery .	[ "This", "finding", "was", "no", "longer", "present", "at", "the", "end", "of", "recovery", "." ]	[ "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	Repeated oral administrations of 20 mg / kg / d were clinically tolerated over 7 days .	[ "Repeated", "oral", "administrations", "of", "20", "mg", "/", "kg", "/", "d", "were", "clinically", "tolerated", "over", "7", "days", "." ]	[ "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	COMPOUND_XXX was administered by dermal skin painting to the dorsal surface ( approximately 10 % of total body surface area ) of CD - 1 mice ( 5 / sex / group ) at dose levels of 100 , 200 or 270 mg / kg for at least 28 days .	[ "COMPOUND_XXX", "was", "administered", "by", "dermal", "skin", "painting", "to", "the", "dorsal", "surface", "(", "approximately", "10", "%", "of", "total", "body", "surface", "area", ")", "of", "CD", "-", "1", "mice", "(", "5", "/", "sex", "/", "group", ")", "at", "dose", "levels", "of", "100", ",", "200", "or", "270", "mg", "/", "kg", "for", "at", "least", "28", "days", "." ]	[ "O", "O", "O", "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", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "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, 12, 13, 13, 13, 13, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The test item , COMPOUND_XXX ( lactate salt ) Batch No .	[ "The", "test", "item", ",", "COMPOUND_XXX", "(", "lactate", "salt", ")", "Batch", "No", "." ]	[ "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	There were no other effects on body weights or absolute body weight gains for males or females at doses : : : : ; 0.3 mglkg after the first dosing cycle .	[ "There", "were", "no", "other", "effects", "on", "body", "weights", "or", "absolute", "body", "weight", "gains", "for", "males", "or", "females", "at", "doses", ":", ":", ":", ":", ";", "0.3", "mglkg", "after", "the", "first", "dosing", "cycle", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "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 ]
PRETOX_REL	Changes unrelated to COMPOUND_XXX : None Body Weights ( Tables 2 - 1 to 2 - 3 , Appendices 2 - 1 to 2 - 12 ) Changes related to COMPOUND_XXX : At 50 mg / kg , significant decreases were noted on Day 29 , and increases were noted on Days 64 to 78 , and 113 to 134 compared to the controls .	[ "Changes", "unrelated", "to", "COMPOUND_XXX", ":", "None", "Body", "Weights", "(", "Tables", "2", "-", "1", "to", "2", "-", "3", ",", "Appendices", "2", "-", "1", "to", "2", "-", "12", ")", "Changes", "related", "to", "COMPOUND_XXX", ":", "At", "50", "mg", "/", "kg", ",", "significant", "decreases", "were", "noted", "on", "Day", "29", ",", "and", "increases", "were", "noted", "on", "Days", "64", "to", "78", ",", "and", "113", "to", "134", "compared", "to", "the", "controls", "." ]	[ "O", "O", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "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", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 2, 6, 0, 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, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The batch used for this study was XXXXXX .	[ "The", "batch", "used", "for", "this", "study", "was", "XXXXXX", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	It is considered not to represent a potential risk to man .	[ "It", "is", "considered", "not", "to", "represent", "a", "potential", "risk", "to", "man", "." ]	[ "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 concentration of the week 13 low dose formulation was outside of specification ( 116 % of target ) .	[ "The", "concentration", "of", "the", "week", "13", "low", "dose", "formulation", "was", "outside", "of", "specification", "(", "116", "%", "of", "target", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The AUC 5min - 3h also increased over - proportionally in relation to the dose increase between 0.1 and 1.0 mg / kg .	[ "The", "AUC", "5min", "-", "3h", "also", "increased", "over", "-", "proportionally", "in", "relation", "to", "the", "dose", "increase", "between", "0.1", "and", "1.0", "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", "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, 4, 4, 0 ]
NO_PRETOX_REL	Conclusion / Discussion A NOAEL could not be determined under the conditions of the study .	[ "Conclusion", "/", "Discussion", "A", "NOAEL", "could", "not", "be", "determined", "under", "the", "conditions", "of", "the", "study", "." ]	[ "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 ]
NO_PRETOX_REL	Therefore , under these study conditions , the dose of 10 mg / kg / day was considered to be a NoObserved Effect Level ( NOEL ) and the dose of 30 mg / kg / day was considered to be a NoObserved Adverse Effect Level ( NOAEL ) based on urinalysis variations and minimal microscopic findings in the diaphragm .	[ "Therefore", ",", "under", "these", "study", "conditions", ",", "the", "dose", "of", "10", "mg", "/", "kg", "/", "day", "was", "considered", "to", "be", "a", "NoObserved", "Effect", "Level", "(", "NOEL", ")", "and", "the", "dose", "of", "30", "mg", "/", "kg", "/", "day", "was", "considered", "to", "be", "a", "NoObserved", "Adverse", "Effect", "Level", "(", "NOAEL", ")", "based", "on", "urinalysis", "variations", "and", "minimal", "microscopic", "findings", "in", "the", "diaphragm", "." ]	[ "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", "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", "O", "O", "O" ]	[ 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, 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, 0, 0, 0 ]
NO_PRETOX_REL	Results Formulation analysis revealed that the dose groups were sufficiently exposed to the test item : The animals received mostly the anticipated concentrations ( 85 – 115 % ) , with the exception of 3 samples with concentrations that were slightly above the predefined acceptance limit .	[ "Results", "Formulation", "analysis", "revealed", "that", "the", "dose", "groups", "were", "sufficiently", "exposed", "to", "the", "test", "item", ":", "The", "animals", "received", "mostly", "the", "anticipated", "concentrations", "(", "85", "–", "115", "%", ")", ",", "with", "the", "exception", "of", "3", "samples", "with", "concentrations", "that", "were", "slightly", "above", "the", "predefined", "acceptance", "limit", "." ]	[ "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", "O", "O", "O", "O", "O", "O", "O" ]	[ 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, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	RESULTS General findings Tests of the reflexes showed no adverse effects up to and including group Ul { individual data see appendix of the report ) .	[ "RESULTS", "General", "findings", "Tests", "of", "the", "reflexes", "showed", "no", "adverse", "effects", "up", "to", "and", "including", "group", "Ul", "{", "individual", "data", "see", "appendix", "of", "the", "report", ")", "." ]	[ "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" ]	[ 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 ]
NO_PRETOX_REL	Following oral administration , COMPOUND_XXX was quickly absorbed reaching peak plasma concentrations in approximately 0.5 to 2 hours .	[ "Following", "oral", "administration", ",", "COMPOUND_XXX", "was", "quickly", "absorbed", "reaching", "peak", "plasma", "concentrations", "in", "approximately", "0.5", "to", "2", "hours", "." ]	[ "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	A mild to moderate increase in circulating lymphocytes and neutrophils was seen .	[ "A", "mild", "to", "moderate", "increase", "in", "circulating", "lymphocytes", "and", "neutrophils", "was", "seen", "." ]	[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "O", "O" ]	[ 0, 0, 0, 0, 1, 0, 0, 2, 0, 2, 0, 0, 0 ]
PRETOX_REL	Increases in cardiac troponin I in animals treated with COMPOUND_XXX indicated cardiotoxicity at 180 mg / kg / day and correlated with histological changes in the heart .	[ "Increases", "in", "cardiac", "troponin", "I", "in", "animals", "treated", "with", "COMPOUND_XXX", "indicated", "cardiotoxicity", "at", "180", "mg", "/", "kg", "/", "day", "and", "correlated", "with", "histological", "changes", "in", "the", "heart", "." ]	[ "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O" ]	[ 1, 0, 2, 6, 6, 0, 0, 0, 0, 0, 0, 8, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 8, 9, 0, 0, 10, 0 ]
PRETOX_REL	Organ weight changes were noted at 60 mg / kg / day , including increased heart and kidney weights in both sexes and increased liver and decreased thyroid weights in females only .	[ "Organ", "weight", "changes", "were", "noted", "at", "60", "mg", "/", "kg", "/", "day", ",", "including", "increased", "heart", "and", "kidney", "weights", "in", "both", "sexes", "and", "increased", "liver", "and", "decreased", "thyroid", "weights", "in", "females", "only", "." ]	[ "B-SPECIMEN", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "I-SEX", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SEX", "O", "O" ]	[ 10, 2, 1, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 1, 10, 0, 10, 2, 0, 5, 7, 0, 1, 10, 0, 1, 10, 2, 0, 5, 0, 0 ]
NO_PRETOX_REL	Groups of 8 or 10 male control animals similarly received the above mentioned vehicle at 5 mL / kg for 3 days or 4 weeks , respectively .	[ "Groups", "of", "8", "or", "10", "male", "control", "animals", "similarly", "received", "the", "above", "mentioned", "vehicle", "at", "5", "mL", "/", "kg", "for", "3", "days", "or", "4", "weeks", ",", "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" ]	[ 0, 0, 0, 0, 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	Minimally higher liver weights were noted from the low dose in females with , in addition , pale liver for some females at 320 mg / kg .	[ "Minimally", "higher", "liver", "weights", "were", "noted", "from", "the", "low", "dose", "in", "females", "with", ",", "in", "addition", ",", "pale", "liver", "for", "some", "females", "at", "320", "mg", "/", "kg", "." ]	[ "O", "B-MANIFESTATION_FINDING", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-SEX", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 1, 10, 2, 0, 0, 0, 0, 15, 16, 0, 5, 0, 0, 0, 0, 0, 8, 9, 0, 0, 5, 0, 3, 4, 4, 4, 0 ]
NO_PRETOX_REL	Organ weights No compound related findings .	[ "Organ", "weights", "No", "compound", "related", "findings", "." ]	[ "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Clinical signs , body weight and food consumption determinations were performed on all the animals .	[ "Clinical", "signs", ",", "body", "weight", "and", "food", "consumption", "determinations", "were", "performed", "on", "all", "the", "animals", "." ]	[ "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 ]
NO_PRETOX_REL	The toxicological relevance of these findings is debatable .	[ "The", "toxicological", "relevance", "of", "these", "findings", "is", "debatable", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Test article - related moribundity occurred during week 3 in one female at 80 mg / kg / day following approximately 9 daily doses .	[ "Test", "article", "-", "related", "moribundity", "occurred", "during", "week", "3", "in", "one", "female", "at", "80", "mg", "/", "kg", "/", "day", "following", "approximately", "9", "daily", "doses", "." ]	[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Selected clinical chemistry parameters were determined at the end of the study .	[ "Selected", "clinical", "chemistry", "parameters", "were", "determined", "at", "the", "end", "of", "the", "study", "." ]	[ "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 ]
NO_PRETOX_REL	Complete necropsies including macroscopic assessments were performed on all animals .	[ "Complete", "necropsies", "including", "macroscopic", "assessments", "were", "performed", "on", "all", "animals", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	During the recovery period , food consumption was also reduced in animals treated with 10 umol / kg bw .	[ "During", "the", "recovery", "period", ",", "food", "consumption", "was", "also", "reduced", "in", "animals", "treated", "with", "10", "umol", "/", "kg", "bw", "." ]	[ "O", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 2, 6, 0, 0, 1, 0, 0, 0, 0, 3, 4, 4, 4, 4, 0 ]
PRETOX_REL	At histopathology the female rats of all dose groups ( 3 , 10 , and 30 mg / kg ) exhibited a cytoplasmatic vacuolation in the zona fasciculata of the adrenal gland .	[ "At", "histopathology", "the", "female", "rats", "of", "all", "dose", "groups", "(", "3", ",", "10", ",", "and", "30", "mg", "/", "kg", ")", "exhibited", "a", "cytoplasmatic", "vacuolation", "in", "the", "zona", "fasciculata", "of", "the", "adrenal", "gland", "." ]	[ "O", "O", "O", "B-SEX", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 5, 0, 0, 12, 13, 13, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0, 0, 10, 11, 0 ]
NO_PRETOX_REL	D6 is an intermediate of drug synthesis and has shown to be mutagenic in the AMES test .	[ "D6", "is", "an", "intermediate", "of", "drug", "synthesis", "and", "has", "shown", "to", "be", "mutagenic", "in", "the", "AMES", "test", "." ]	[ "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	Notable body weight losses occurred in individual animals as early as day 15 and persisted and / or worsened on days 22 , 26 and 29 .	[ "Notable", "body", "weight", "losses", "occurred", "in", "individual", "animals", "as", "early", "as", "day", "15", "and", "persisted", "and", "/", "or", "worsened", "on", "days", "22", ",", "26", "and", "29", "." ]	[ "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 2, 6, 1, 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	An additional 36 animals / sex / group received 100 , 200 or 270 mg / kg daily for toxicokinetic evaluations on Days 1 and 28 .	[ "An", "additional", "36", "animals", "/", "sex", "/", "group", "received", "100", ",", "200", "or", "270", "mg", "/", "kg", "daily", "for", "toxicokinetic", "evaluations", "on", "Days", "1", "and", "28", "." ]	[ "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 12, 13, 13, 13, 13, 13, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The increase in the liver weight ratio in males from group I ~ II are considered to be spontaneous in origin as no histopathological alterations occurred in the liver of male animals .	[ "The", "increase", "in", "the", "liver", "weight", "ratio", "in", "males", "from", "group", "I", "~", "II", "are", "considered", "to", "be", "spontaneous", "in", "origin", "as", "no", "histopathological", "alterations", "occurred", "in", "the", "liver", "of", "male", "animals", "." ]	[ "O", "B-MANIFESTATION_FINDING", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "B-SEX", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 1, 0, 0, 10, 2, 0, 0, 5, 0, 12, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	At 25 mg / kg , significant decreases were noted on Days 50 to 64 , and increases were noted on Days 113 to 141 , 155 , 176 , and 183 compared to the controls .	[ "At", "25", "mg", "/", "kg", ",", "significant", "decreases", "were", "noted", "on", "Days", "50", "to", "64", ",", "and", "increases", "were", "noted", "on", "Days", "113", "to", "141", ",", "155", ",", "176", ",", "and", "183", "compared", "to", "the", "controls", "." ]	[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "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, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	T4 levels were decreased in male and female rats .	[ "T4", "levels", "were", "decreased", "in", "male", "and", "female", "rats", "." ]	[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O" ]	[ 2, 6, 0, 1, 0, 5, 7, 7, 0, 0 ]
PRETOX_REL	In group III , the heart rates were increased in both sexes in week 1 and 4 two hours after application respectively .	[ "In", "group", "III", ",", "the", "heart", "rates", "were", "increased", "in", "both", "sexes", "in", "week", "1", "and", "4", "two", "hours", "after", "application", "respectively", "." ]	[ "O", "B-GROUP", "I-GROUP", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-SEX", "I-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 12, 13, 0, 0, 8, 9, 9, 9, 0, 5, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	A further group received 2000 mg / kg / day subdivided into 2 equal doses , separated by 1 hour .	[ "A", "further", "group", "received", "2000", "mg", "/", "kg", "/", "day", "subdivided", "into", "2", "equal", "doses", ",", "separated", "by", "1", "hour", "." ]	[ "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" ]	[ 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Relative liver weight was increased in both males and females .	[ "Relative", "liver", "weight", "was", "increased", "in", "both", "males", "and", "females", "." ]	[ "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O" ]	[ 0, 10, 2, 0, 1, 0, 0, 5, 7, 7, 0 ]
PRETOX_REL	At post-mortem , animals given 1000 mg / kg / day had swollen hindlimbs with restricted movement of the joints .	[ "At", "post-mortem", ",", "animals", "given", "1000", "mg", "/", "kg", "/", "day", "had", "swollen", "hindlimbs", "with", "restricted", "movement", "of", "the", "joints", "." ]	[ "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 8, 9, 0, 8, 9, 0, 0, 10, 0 ]
PRETOX_REL	Regarding clinical chemistry parameters , the increased GLDH observed only in one 30 mg / kg female was considered incidental .	[ "Regarding", "clinical", "chemistry", "parameters", ",", "the", "increased", "GLDH", "observed", "only", "in", "one", "30", "mg", "/", "kg", "female", "was", "considered", "incidental", "." ]	[ "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "B-SEX", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 3, 4, 4, 4, 5, 0, 0, 0, 0 ]
PRETOX_REL	From macroscopic and microscopic observations at premature and / or terminal kill , degenerative / atrophic changes were seen in the haemolymphopoietic system , lungs , intestines and ovaries mainly at the dose level of 40 mg / kg and were considered as toxicological targets of the compound COMPOUND_XXX as follows : - the bone marrow hypocellularity was noted in all animals given 40 mg / kg and was the histological correlate of the fluid femoral bone marrow seen for 5/10 males and 4/7 prematurely killed females given 40 mg / kg .	[ "From", "macroscopic", "and", "microscopic", "observations", "at", "premature", "and", "/", "or", "terminal", "kill", ",", "degenerative", "/", "atrophic", "changes", "were", "seen", "in", "the", "haemolymphopoietic", "system", ",", "lungs", ",", "intestines", "and", "ovaries", "mainly", "at", "the", "dose", "level", "of", "40", "mg", "/", "kg", "and", "were", "considered", "as", "toxicological", "targets", "of", "the", "compound", "COMPOUND_XXX", "as", "follows", ":", "-", "the", "bone", "marrow", "hypocellularity", "was", "noted", "in", "all", "animals", "given", "40", "mg", "/", "kg", "and", "was", "the", "histological", "correlate", "of", "the", "fluid", "femoral", "bone", "marrow", "seen", "for", "5/10", "males", "and", "4/7", "prematurely", "killed", "females", "given", "40", "mg", "/", "kg", "." ]	[ "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "B-SPECIMEN", "O", "B-SPECIMEN", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-SEX", "O", "O", "B-FINDING", "I-FINDING", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 0, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0, 8, 9, 9, 9, 0, 0, 0, 0, 10, 11, 0, 10, 11, 10, 0, 10, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 9, 0, 0, 0, 5, 0, 0, 8, 9, 5, 0, 3, 4, 4, 4, 0 ]
NO_PRETOX_REL	Clinical Pathology : There were no clinical chemistry or hematology changes in rats given 40 or 160 mg / kg / day .	[ "Clinical", "Pathology", ":", "There", "were", "no", "clinical", "chemistry", "or", "hematology", "changes", "in", "rats", "given", "40", "or", "160", "mg", "/", "kg", "/", "day", "." ]	[ "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", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	Additionally one sample was obtained for all animals 24 hours after dosing on one occasion in Week 26 .	[ "Additionally", "one", "sample", "was", "obtained", "for", "all", "animals", "24", "hours", "after", "dosing", "on", "one", "occasion", "in", "Week", "26", "." ]	[ "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	SUMMARY AND CONCLUSIONS : Plasma samples from rats on days 1 , 15 and 29 of treatment with 0 ( vehicle control ) , 0 ( distilled water control ) , 10 , 40 , 180 or in mg / kg / day for 29 days ( protocol 05591 ) were analyzed by a solvent extraction - HPLC / UV method .	[ "SUMMARY", "AND", "CONCLUSIONS", ":", "Plasma", "samples", "from", "rats", "on", "days", "1", ",", "15", "and", "29", "of", "treatment", "with", "0", "(", "vehicle", "control", ")", ",", "0", "(", "distilled", "water", "control", ")", ",", "10", ",", "40", ",", "180", "or", "in", "mg", "/", "kg", "/", "day", "for", "29", "days", "(", "protocol", "05591", ")", "were", "analyzed", "by", "a", "solvent", "extraction", "-", "HPLC", "/", "UV", "method", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "O", "B-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "I-GROUP", "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", "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, 12, 13, 13, 13, 13, 0, 12, 13, 13, 13, 13, 13, 0, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	All male animals were interim sacrificed on day 10 of the test with regard to clear signs of liver toxicity detected in biochemical examinations on day 8 .	[ "All", "male", "animals", "were", "interim", "sacrificed", "on", "day", "10", "of", "the", "test", "with", "regard", "to", "clear", "signs", "of", "liver", "toxicity", "detected", "in", "biochemical", "examinations", "on", "day", "8", "." ]	[ "O", "B-SEX", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 5, 0, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Food consumption was significantly reduced as compared to controls in males and females administered the 0.9 mg / kg dose at the end of the first , third and / or fourth dosing cycles .	[ "Food", "consumption", "was", "significantly", "reduced", "as", "compared", "to", "controls", "in", "males", "and", "females", "administered", "the", "0.9", "mg", "/", "kg", "dose", "at", "the", "end", "of", "the", "first", ",", "third", "and", "/", "or", "fourth", "dosing", "cycles", "." ]	[ "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "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" ]	[ 2, 6, 0, 0, 1, 0, 0, 0, 0, 0, 5, 7, 7, 0, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	A control group of 3 male and 3 females received empty capsules during the treatment period and then no capsules during the recovery period .	[ "A", "control", "group", "of", "3", "male", "and", "3", "females", "received", "empty", "capsules", "during", "the", "treatment", "period", "and", "then", "no", "capsules", "during", "the", "recovery", "period", "." ]	[ "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" ]	[ 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 ]
NO_PRETOX_REL	At the initiation of dosing , the animals were approximately 8 weeks of age and weighed 219.5 to 261.5 g for males and 160.6 to 196.7 g for females .	[ "At", "the", "initiation", "of", "dosing", ",", "the", "animals", "were", "approximately", "8", "weeks", "of", "age", "and", "weighed", "219.5", "to", "261.5", "g", "for", "males", "and", "160.6", "to", "196.7", "g", "for", "females", "." ]	[ "O", "O", "O", "O", "O", "O", "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 ]
NO_PRETOX_REL	Control animals received 1 % CMC only .	[ "Control", "animals", "received", "1", "%", "CMC", "only", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The increase in exposure was generally doseproportional in both male and female animals .	[ "The", "increase", "in", "exposure", "was", "generally", "doseproportional", "in", "both", "male", "and", "female", "animals", "." ]	[ "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 ]
PRETOX_REL	However , the neurodegeneration induced by COMPOUND_XXX can not be regarded as a gender - specific effect since males and females were similarly affected in a 5 - day dose range - finding toxicity study [ 1 ] .	[ "However", ",", "the", "neurodegeneration", "induced", "by", "COMPOUND_XXX", "can", "not", "be", "regarded", "as", "a", "gender", "-", "specific", "effect", "since", "males", "and", "females", "were", "similarly", "affected", "in", "a", "5", "-", "day", "dose", "range", "-", "finding", "toxicity", "study", "[", "1", "]", "." ]	[ "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 7, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The purpose of this study was to establish the toxicologic effects of COMPOUND_XXX , a histone deacetylase inhibitor , when administered intravenously to rats for 13 weeks using a once weekly dosing schedule .

[ "The", "purpose", "of", "this", "study", "was", "to", "establish", "the", "toxicologic", "effects", "of", "COMPOUND_XXX", ",", "a", "histone", "deacetylase", "inhibitor", ",", "when", "administered", "intravenously", "to", "rats", "for", "13", "weeks", "using", "a", "once", "weekly", "dosing", "schedule", "." ]

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

PRETOX_REL

vomit and hypersalivation in males and females treated at 75 mg / kg / day , .

[ "vomit", "and", "hypersalivation", "in", "males", "and", "females", "treated", "at", "75", "mg", "/", "kg", "/", "day", ",", "." ]

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

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

PRETOX_REL

Sporadic food left was observed at 25 mg / kg and higher .

[ "Sporadic", "food", "left", "was", "observed", "at", "25", "mg", "/", "kg", "and", "higher", "." ]

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

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

NO_PRETOX_REL

Concerning the water intake , there were no descriptions of unusual findings in water intake in the observation records .

[ "Concerning", "the", "water", "intake", ",", "there", "were", "no", "descriptions", "of", "unusual", "findings", "in", "water", "intake", "in", "the", "observation", "records", "." ]

[ "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

Three groups will be treated with one formulation at three different concentrations ( 0 % , 10 % and 20 % ) .

[ "Three", "groups", "will", "be", "treated", "with", "one", "formulation", "at", "three", "different", "concentrations", "(", "0", "%", ",", "10", "%", "and", "20", "%", ")", "." ]

[ "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 ]

PRETOX_REL

Rales was occasionally observed in the 600 and 2000 mgikgíday groups one hour following dosing .

[ "Rales", "was", "occasionally", "observed", "in", "the", "600", "and", "2000", "mgikgíday", "groups", "one", "hour", "following", "dosing", "." ]

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

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

PRETOX_REL

In animals with renal changes , the bone changes were complicated by secondary increases in bone resorption of tibia and alveolar bones .

[ "In", "animals", "with", "renal", "changes", ",", "the", "bone", "changes", "were", "complicated", "by", "secondary", "increases", "in", "bone", "resorption", "of", "tibia", "and", "alveolar", "bones", "." ]

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

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

PRETOX_REL

Statistically significant drug - related decrease in body weight gains were detected in the high dose males ( 15 % ) and low ( 10 % ) , mid ( 10 % ) and high dose ( 27 % ) females .

[ "Statistically", "significant", "drug", "-", "related", "decrease", "in", "body", "weight", "gains", "were", "detected", "in", "the", "high", "dose", "males", "(", "15", "%", ")", "and", "low", "(", "10", "%", ")", ",", "mid", "(", "10", "%", ")", "and", "high", "dose", "(", "27", "%", ")", "females", "." ]

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NO_PRETOX_REL

The present data set gives no indication of gender - specific differences in pharmacokinetics of COMPOUND_XXX in minipigs .

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

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PRETOX_REL

The spermatogenesis was markedly impaired .

[ "The", "spermatogenesis", "was", "markedly", "impaired", "." ]

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

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

PRETOX_REL

Adrenal cortical alterations increased with treatment duration and included vacuolation , hypertrophy , single cell necrosis , hemorrhage / congestion and inflammatory cell infiltration and after the recovery period pigment deposition .

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PRETOX_REL

In conclusion , treatment with COMPOUND_XXX caused a notably high early mortality at a dose of 600 mg / kg / day , a dose - related decrease in serum glucose , and minimal to mild axonal degeneration in sciatic ( peripheral ) nerves of rats treated with 100 , 300 , or 600 mg / kg / day of COMPOUND_XXX .

[ "In", "conclusion", ",", "treatment", "with", "COMPOUND_XXX", "caused", "a", "notably", "high", "early", "mortality", "at", "a", "dose", "of", "600", "mg", "/", "kg", "/", "day", ",", "a", "dose", "-", "related", "decrease", "in", "serum", "glucose", ",", "and", "minimal", "to", "mild", "axonal", "degeneration", "in", "sciatic", "(", "peripheral", ")", "nerves", "of", "rats", "treated", "with", "100", ",", "300", ",", "or", "600", "mg", "/", "kg", "/", "day", "of", "COMPOUND_XXX", "." ]

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NO_PRETOX_REL

Electron microscopic evaluation of heart tissue from selected animals treated with COMPOUND_XXX at 80 mg / kg for 28 days generally showed the same ultra-morphology of all cellular organelles as the corresponding control animals .

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NO_PRETOX_REL

The dogs in all test article - treated groups were exposed to COMPOUND_XXX .

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

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PRETOX_REL

Electron microscopy revealed the occurrence of myeloid bodies in endothelial cells of heart and skeletal muscle which was distinct to striking and numerous after treatment with COMPOUND_XXX at 180 mg / kg / day .

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

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NO_PRETOX_REL

Various forms of Plasmodium sp , present in rare to occasional numbers , were identified microscopically in Wright 's stained blood films in animals of both sexes at doses ~ 30 mglkg / day and in two low - dose males .

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

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NO_PRETOX_REL

The exposure after approximately 11 and 25 weeks of treatment on a 3 doses / week regime was similar but was higher than exposure on Day 1 .

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

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PRETOX_REL

The principal test article - related microscopic findings consisted of thyroid changes ( ~ 0.06 mg / kg / day ) , depletion of lymphoid tissue ( ~ 0.2 mg / kg / day ) , thymic atrophy ( 0.6 mg / kg / day ) , decreased bone marrow hematopoiesis ( 0.6 mg / kg / day ) , and intracellular pigment deposition at various sites ( ~ 0.2 mg / kg / day ) .

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PRETOX_REL

Slight reductions in body - weight gain and food consumption were observed in males and females given 225 and 500 mgikg / day of NS and in females given 500 mg / kHday of OS .

[ "Slight", "reductions", "in", "body", "-", "weight", "gain", "and", "food", "consumption", "were", "observed", "in", "males", "and", "females", "given", "225", "and", "500", "mgikg", "/", "day", "of", "NS", "and", "in", "females", "given", "500", "mg", "/", "kHday", "of", "OS", "." ]

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PRETOX_REL

At the high dose these lung findings escalated to diffuse foam cell aggregation associated with acute / mixed inflammation and hyperplasia of alveolar type II pneumocytes .

[ "At", "the", "high", "dose", "these", "lung", "findings", "escalated", "to", "diffuse", "foam", "cell", "aggregation", "associated", "with", "acute", "/", "mixed", "inflammation", "and", "hyperplasia", "of", "alveolar", "type", "II", "pneumocytes", "." ]

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

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PRETOX_REL

, 20 Due to a moribund condition animal H 062 / group | had to be sacrificed prematurely at the end of week 13 of the study ( see also , a. Clinical observations " ) .

[ ",", "20", "Due", "to", "a", "moribund", "condition", "animal", "H", "062", "/", "group", "|", "had", "to", "be", "sacrificed", "prematurely", "at", "the", "end", "of", "week", "13", "of", "the", "study", "(", "see", "also", ",", "a.", "Clinical", "observations", "\"", ")", "." ]

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PRETOX_REL

One 30 mg / kg female showed a markedly increased GLDH value ( animal no. 36 ) .

[ "One", "30", "mg", "/", "kg", "female", "showed", "a", "markedly", "increased", "GLDH", "value", "(", "animal", "no.", "36", ")", "." ]

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

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PRETOX_REL

Additionally , all group III ( 30/60 mg / kg ) - males showed a minimal infiltration with granulocytes .

[ "Additionally", ",", "all", "group", "III", "(", "30/60", "mg", "/", "kg", ")", "-", "males", "showed", "a", "minimal", "infiltration", "with", "granulocytes", "." ]

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

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PRETOX_REL

As can be seen from the table , feed intake was slightly reduced in group Ill - males in comparison to control animals whereas in females no changes were observed up to and including group III .

[ "As", "can", "be", "seen", "from", "the", "table", ",", "feed", "intake", "was", "slightly", "reduced", "in", "group", "Ill", "-", "males", "in", "comparison", "to", "control", "animals", "whereas", "in", "females", "no", "changes", "were", "observed", "up", "to", "and", "including", "group", "III", "." ]

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PRETOX_REL

Increased serum TSH levels and increased relative kidney weights were observed in female rats .

[ "Increased", "serum", "TSH", "levels", "and", "increased", "relative", "kidney", "weights", "were", "observed", "in", "female", "rats", "." ]

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

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NO_PRETOX_REL

The mechanisms of toxicity and surrogate markers were also evaluated .

[ "The", "mechanisms", "of", "toxicity", "and", "surrogate", "markers", "were", "also", "evaluated", "." ]

[ "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

In uterine samples mean concentrations of COMPOUND_XXX were about 1000 times higher than the highest serum concentrations measured ( TT 1 ) .

[ "In", "uterine", "samples", "mean", "concentrations", "of", "COMPOUND_XXX", "were", "about", "1000", "times", "higher", "than", "the", "highest", "serum", "concentrations", "measured", "(", "TT", "1", ")", "." ]

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

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PRETOX_REL

In addition at the mid dose of 20 mg / kg COMPOUND_XXX per day and higher : Clinical examinations : - emaciation occurred in one male animal of the mid dose .

[ "In", "addition", "at", "the", "mid", "dose", "of", "20", "mg", "/", "kg", "COMPOUND_XXX", "per", "day", "and", "higher", ":", "Clinical", "examinations", ":", "-", "emaciation", "occurred", "in", "one", "male", "animal", "of", "the", "mid", "dose", "." ]

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

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NO_PRETOX_REL

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

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

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

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PRETOX_REL

The only histopathological finding related to COMPOUND_XXX treatment was minimal to slight segmental degeneration of the sciatic nerve in female rats , which was evident in at least one animal at all dose levels .

[ "The", "only", "histopathological", "finding", "related", "to", "COMPOUND_XXX", "treatment", "was", "minimal", "to", "slight", "segmental", "degeneration", "of", "the", "sciatic", "nerve", "in", "female", "rats", ",", "which", "was", "evident", "in", "at", "least", "one", "animal", "at", "all", "dose", "levels", "." ]

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

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NO_PRETOX_REL

Accumulations of granulocytes are absent .

[ "Accumulations", "of", "granulocytes", "are", "absent", "." ]

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

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

PRETOX_REL

Transient local effects at the application site were limited to occasional erythema , mainly at the high dose during the first 9 weeks of the study and a slightly lower body weight gain was noted in treated males of all groups including Placebo Nail Lacquer and in females at 270 mg / kg compared with sham controls .

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NO_PRETOX_REL

On Day I. peak plasma concentrations in males were 266 ± 340 ng / ml , 529 ± 224 ng / ml and 1007 ± 440 ng / ml for 5 , 15 and 60 mg / kg / day respectively .

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NO_PRETOX_REL

After treatment for 2 or 4 weeks , exposure to COMPOUND_XXX or its metabolite COMPOUND_XXX doseproportionally increased from 120 to 180 mg / kg / day while for an under - proportional increased exposure was observed from 5 to 15 mg / kg / day .

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PRETOX_REL

The lesion was characterized by a minimal or slight perivascular edema of larger arteries located in the proximal parts of the papillary muscle .

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PRETOX_REL

Adverse treatment - related effects were limited to slight , reversible degenerative changes in the sciatic nerve of female rats at all dose levels .

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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 .

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NO_PRETOX_REL

There were no clinical signs of toxicity .

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

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

NO_PRETOX_REL

No clinical signs were observed .

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

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

NO_PRETOX_REL

The purpose of this study was to compare the toxicity and toxicokinetic profile of COMPOUND_XXX produced by a new route of chemical synthesis with that produced by the old route of synthesis .

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PRETOX_REL

With the exception of dermal lesions observed at the site of test article administration , no gross pathology findings were considered to be test article related .

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NO_PRETOX_REL

The treatment period was followed by a four - week recovery period to determine the persistence or reversibility of any treatment - related effects .

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PRETOX_REL

Anemia and slight increases in AST and ALT , indicative for hepatocellular damage , were further findings .

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NO_PRETOX_REL

No relevant body and organ weight changes were found in females .

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

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NO_PRETOX_REL

All changes were reversible on withdrawal of treatment .

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

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

PRETOX_REL

Drug - related effects on food consumption were noted in Group · V animals , an approximate 10 - 15 % decrease was noted .

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NO_PRETOX_REL

Clinical pathology evaluations ( hematology including coagulation , clinical chemistry and urinalysis ) were conducted on all animals during pretest and week 4 and at the end of the recovery period .

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NO_PRETOX_REL

Complete coverage of the administration area with the test or reference item generally persisted for 1 to 5 days .

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NO_PRETOX_REL

Hematology and clinical chemistry were performed during the last week of the study .

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NO_PRETOX_REL

On Week 52 .

[ "On", "Week", "52", "." ]

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

[ 0, 0, 0, 0 ]

NO_PRETOX_REL

This finding was no longer present at the end of recovery .

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[ "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

Repeated oral administrations of 20 mg / kg / d were clinically tolerated over 7 days .

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NO_PRETOX_REL

COMPOUND_XXX was administered by dermal skin painting to the dorsal surface ( approximately 10 % of total body surface area ) of CD - 1 mice ( 5 / sex / group ) at dose levels of 100 , 200 or 270 mg / kg for at least 28 days .

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NO_PRETOX_REL

The test item , COMPOUND_XXX ( lactate salt ) Batch No .

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NO_PRETOX_REL

There were no other effects on body weights or absolute body weight gains for males or females at doses : : : : ; 0.3 mglkg after the first dosing cycle .

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PRETOX_REL

Changes unrelated to COMPOUND_XXX : None Body Weights ( Tables 2 - 1 to 2 - 3 , Appendices 2 - 1 to 2 - 12 ) Changes related to COMPOUND_XXX : At 50 mg / kg , significant decreases were noted on Day 29 , and increases were noted on Days 64 to 78 , and 113 to 134 compared to the controls .

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NO_PRETOX_REL

The batch used for this study was XXXXXX .

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

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NO_PRETOX_REL

It is considered not to represent a potential risk to man .

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[ "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 concentration of the week 13 low dose formulation was outside of specification ( 116 % of target ) .

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NO_PRETOX_REL

The AUC 5min - 3h also increased over - proportionally in relation to the dose increase between 0.1 and 1.0 mg / kg .

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NO_PRETOX_REL

Conclusion / Discussion A NOAEL could not be determined under the conditions of the study .

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NO_PRETOX_REL

Therefore , under these study conditions , the dose of 10 mg / kg / day was considered to be a NoObserved Effect Level ( NOEL ) and the dose of 30 mg / kg / day was considered to be a NoObserved Adverse Effect Level ( NOAEL ) based on urinalysis variations and minimal microscopic findings in the diaphragm .

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NO_PRETOX_REL

Results Formulation analysis revealed that the dose groups were sufficiently exposed to the test item : The animals received mostly the anticipated concentrations ( 85 – 115 % ) , with the exception of 3 samples with concentrations that were slightly above the predefined acceptance limit .

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NO_PRETOX_REL

RESULTS General findings Tests of the reflexes showed no adverse effects up to and including group Ul { individual data see appendix of the report ) .

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[ "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" ]

[ 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 ]

NO_PRETOX_REL

Following oral administration , COMPOUND_XXX was quickly absorbed reaching peak plasma concentrations in approximately 0.5 to 2 hours .

[ "Following", "oral", "administration", ",", "COMPOUND_XXX", "was", "quickly", "absorbed", "reaching", "peak", "plasma", "concentrations", "in", "approximately", "0.5", "to", "2", "hours", "." ]

[ "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

A mild to moderate increase in circulating lymphocytes and neutrophils was seen .

[ "A", "mild", "to", "moderate", "increase", "in", "circulating", "lymphocytes", "and", "neutrophils", "was", "seen", "." ]

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

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

PRETOX_REL

Increases in cardiac troponin I in animals treated with COMPOUND_XXX indicated cardiotoxicity at 180 mg / kg / day and correlated with histological changes in the heart .

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

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

PRETOX_REL

Organ weight changes were noted at 60 mg / kg / day , including increased heart and kidney weights in both sexes and increased liver and decreased thyroid weights in females only .

[ "Organ", "weight", "changes", "were", "noted", "at", "60", "mg", "/", "kg", "/", "day", ",", "including", "increased", "heart", "and", "kidney", "weights", "in", "both", "sexes", "and", "increased", "liver", "and", "decreased", "thyroid", "weights", "in", "females", "only", "." ]

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

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NO_PRETOX_REL

Groups of 8 or 10 male control animals similarly received the above mentioned vehicle at 5 mL / kg for 3 days or 4 weeks , respectively .

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

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PRETOX_REL

Minimally higher liver weights were noted from the low dose in females with , in addition , pale liver for some females at 320 mg / kg .

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NO_PRETOX_REL

Organ weights No compound related findings .

[ "Organ", "weights", "No", "compound", "related", "findings", "." ]

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

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

NO_PRETOX_REL

Clinical signs , body weight and food consumption determinations were performed on all the animals .

[ "Clinical", "signs", ",", "body", "weight", "and", "food", "consumption", "determinations", "were", "performed", "on", "all", "the", "animals", "." ]

[ "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 ]

NO_PRETOX_REL

The toxicological relevance of these findings is debatable .

[ "The", "toxicological", "relevance", "of", "these", "findings", "is", "debatable", "." ]

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

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

PRETOX_REL

Test article - related moribundity occurred during week 3 in one female at 80 mg / kg / day following approximately 9 daily doses .

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

NO_PRETOX_REL

Selected clinical chemistry parameters were determined at the end of the study .

[ "Selected", "clinical", "chemistry", "parameters", "were", "determined", "at", "the", "end", "of", "the", "study", "." ]

[ "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 ]

NO_PRETOX_REL

Complete necropsies including macroscopic assessments were performed on all animals .

[ "Complete", "necropsies", "including", "macroscopic", "assessments", "were", "performed", "on", "all", "animals", "." ]

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

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

PRETOX_REL

During the recovery period , food consumption was also reduced in animals treated with 10 umol / kg bw .

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

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

PRETOX_REL

At histopathology the female rats of all dose groups ( 3 , 10 , and 30 mg / kg ) exhibited a cytoplasmatic vacuolation in the zona fasciculata of the adrenal gland .

[ "At", "histopathology", "the", "female", "rats", "of", "all", "dose", "groups", "(", "3", ",", "10", ",", "and", "30", "mg", "/", "kg", ")", "exhibited", "a", "cytoplasmatic", "vacuolation", "in", "the", "zona", "fasciculata", "of", "the", "adrenal", "gland", "." ]

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NO_PRETOX_REL

D6 is an intermediate of drug synthesis and has shown to be mutagenic in the AMES test .

[ "D6", "is", "an", "intermediate", "of", "drug", "synthesis", "and", "has", "shown", "to", "be", "mutagenic", "in", "the", "AMES", "test", "." ]

[ "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

Notable body weight losses occurred in individual animals as early as day 15 and persisted and / or worsened on days 22 , 26 and 29 .

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

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NO_PRETOX_REL

An additional 36 animals / sex / group received 100 , 200 or 270 mg / kg daily for toxicokinetic evaluations on Days 1 and 28 .

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

PRETOX_REL

The increase in the liver weight ratio in males from group I ~ II are considered to be spontaneous in origin as no histopathological alterations occurred in the liver of male animals .

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NO_PRETOX_REL

At 25 mg / kg , significant decreases were noted on Days 50 to 64 , and increases were noted on Days 113 to 141 , 155 , 176 , and 183 compared to the controls .

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PRETOX_REL

T4 levels were decreased in male and female rats .

[ "T4", "levels", "were", "decreased", "in", "male", "and", "female", "rats", "." ]

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

[ 2, 6, 0, 1, 0, 5, 7, 7, 0, 0 ]

PRETOX_REL

In group III , the heart rates were increased in both sexes in week 1 and 4 two hours after application respectively .

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

[ 0, 12, 13, 0, 0, 8, 9, 9, 9, 0, 5, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

A further group received 2000 mg / kg / day subdivided into 2 equal doses , separated by 1 hour .

[ "A", "further", "group", "received", "2000", "mg", "/", "kg", "/", "day", "subdivided", "into", "2", "equal", "doses", ",", "separated", "by", "1", "hour", "." ]

[ "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" ]

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PRETOX_REL

Relative liver weight was increased in both males and females .

[ "Relative", "liver", "weight", "was", "increased", "in", "both", "males", "and", "females", "." ]

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

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

PRETOX_REL

At post-mortem , animals given 1000 mg / kg / day had swollen hindlimbs with restricted movement of the joints .

[ "At", "post-mortem", ",", "animals", "given", "1000", "mg", "/", "kg", "/", "day", "had", "swollen", "hindlimbs", "with", "restricted", "movement", "of", "the", "joints", "." ]

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

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

PRETOX_REL

Regarding clinical chemistry parameters , the increased GLDH observed only in one 30 mg / kg female was considered incidental .

[ "Regarding", "clinical", "chemistry", "parameters", ",", "the", "increased", "GLDH", "observed", "only", "in", "one", "30", "mg", "/", "kg", "female", "was", "considered", "incidental", "." ]

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

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

PRETOX_REL

From macroscopic and microscopic observations at premature and / or terminal kill , degenerative / atrophic changes were seen in the haemolymphopoietic system , lungs , intestines and ovaries mainly at the dose level of 40 mg / kg and were considered as toxicological targets of the compound COMPOUND_XXX as follows : - the bone marrow hypocellularity was noted in all animals given 40 mg / kg and was the histological correlate of the fluid femoral bone marrow seen for 5/10 males and 4/7 prematurely killed females given 40 mg / kg .

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NO_PRETOX_REL

Clinical Pathology : There were no clinical chemistry or hematology changes in rats given 40 or 160 mg / kg / day .

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NO_PRETOX_REL

Additionally one sample was obtained for all animals 24 hours after dosing on one occasion in Week 26 .

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NO_PRETOX_REL

SUMMARY AND CONCLUSIONS : Plasma samples from rats on days 1 , 15 and 29 of treatment with 0 ( vehicle control ) , 0 ( distilled water control ) , 10 , 40 , 180 or in mg / kg / day for 29 days ( protocol 05591 ) were analyzed by a solvent extraction - HPLC / UV method .

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PRETOX_REL

All male animals were interim sacrificed on day 10 of the test with regard to clear signs of liver toxicity detected in biochemical examinations on day 8 .

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PRETOX_REL

Food consumption was significantly reduced as compared to controls in males and females administered the 0.9 mg / kg dose at the end of the first , third and / or fourth dosing cycles .

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NO_PRETOX_REL

A control group of 3 male and 3 females received empty capsules during the treatment period and then no capsules during the recovery period .

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NO_PRETOX_REL

At the initiation of dosing , the animals were approximately 8 weeks of age and weighed 219.5 to 261.5 g for males and 160.6 to 196.7 g for females .

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NO_PRETOX_REL

Control animals received 1 % CMC only .

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

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NO_PRETOX_REL

The increase in exposure was generally doseproportional in both male and female animals .

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

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PRETOX_REL

However , the neurodegeneration induced by COMPOUND_XXX can not be regarded as a gender - specific effect since males and females were similarly affected in a 5 - day dose range - finding toxicity study [ 1 ] .

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