javicorvi/pretoxtm-dataset · Datasets at Hugging Face

label stringclasses 2 values	text stringlengths 1 1.95k	tokens sequencelengths 1 371	ner_tags sequencelengths 1 371	ner_tag_codes sequencelengths 1 371
PRETOX_REL	At 3 mg / kg , a pronounced decrease of terminal body weight and of absolute and relative thymus and spleen weights were found in one male .	[ "At", "3", "mg", "/", "kg", ",", "a", "pronounced", "decrease", "of", "terminal", "body", "weight", "and", "of", "absolute", "and", "relative", "thymus", "and", "spleen", "weights", "were", "found", "in", "one", "male", "." ]	[ "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-SEX", "O" ]	[ 0, 3, 4, 4, 4, 0, 0, 0, 1, 0, 2, 6, 6, 0, 0, 0, 0, 0, 10, 0, 10, 2, 0, 0, 0, 0, 5, 0 ]
PRETOX_REL	The main finding was atrophy of epithelium in various organs , often accompanied by inflammation .	[ "The", "main", "finding", "was", "atrophy", "of", "epithelium", "in", "various", "organs", ",", "often", "accompanied", "by", "inflammation", "." ]	[ "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "O", "B-FINDING", "I-FINDING" ]	[ 0, 0, 0, 0, 8, 9, 9, 0, 10, 11, 0, 0, 0, 0, 8, 9 ]
NO_PRETOX_REL	_ The evaluation of blood pressure and of heart rates ( for individual and mean values see â € ™ appendix of the report ) showed no adverse effects up to and including group ltl .	[ "_", "The", "evaluation", "of", "blood", "pressure", "and", "of", "heart", "rates", "(", "for", "individual", "and", "mean", "values", "see", "â", "€", "™", "appendix", "of", "the", "report", ")", "showed", "no", "adverse", "effects", "up", "to", "and", "including", "group", "ltl", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL	No relevant changes were found in females .	[ "No", "relevant", "changes", "were", "found", "in", "females", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 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 ]
PRETOX_REL	Increases in aspartate aminotransferase were present at doses of 1.0 mg / kg / occasion but lacked any microscopic correlate .	[ "Increases", "in", "aspartate", "aminotransferase", "were", "present", "at", "doses", "of", "1.0", "mg", "/", "kg", "/", "occasion", "but", "lacked", "any", "microscopic", "correlate", "." ]	[ "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O" ]	[ 1, 0, 2, 6, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	There were no test article - related effects on clinical pathology parameters ( hematology , serum chemistry or urinalysis ) .	[ "There", "were", "no", "test", "article", "-", "related", "effects", "on", "clinical", "pathology", "parameters", "(", "hematology", ",", "serum", "chemistry", "or", "urinalysis", ")", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Peripheral neuropathy has been observed in rats subjected to a continuous 72 hour insulin infusion in which glucose levels of approximately 2.5 mM ( 45 mg / dl ) were sustained [ 5 ] .	[ "Peripheral", "neuropathy", "has", "been", "observed", "in", "rats", "subjected", "to", "a", "continuous", "72", "hour", "insulin", "infusion", "in", "which", "glucose", "levels", "of", "approximately", "2.5", "mM", "(", "45", "mg", "/", "dl", ")", "were", "sustained", "[", "5", "]", "." ]	[ "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", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 8, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 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	Two group III ( 30/60 mg / kg ) - males showed pigment deposition , and one group III ( 30/60 mg / kg ) - male a small area of acute myocardial necrosis .	[ "Two", "group", "III", "(", "30/60", "mg", "/", "kg", ")", "-", "males", "showed", "pigment", "deposition", ",", "and", "one", "group", "III", "(", "30/60", "mg", "/", "kg", ")", "-", "male", "a", "small", "area", "of", "acute", "myocardial", "necrosis", "." ]	[ "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 0, 12, 13, 0, 3, 4, 4, 4, 0, 0, 5, 0, 8, 9, 0, 0, 0, 12, 13, 0, 3, 4, 4, 4, 0, 0, 5, 0, 0, 0, 0, 8, 9, 9, 0 ]
PRETOX_REL	Additionally , after the high dose of 100 mg / kg COMPOUND_XXX per day : - At necropsy , cystic dilatation of the mesovarium was noted in one animal ( suspected compound - related ) .	[ "Additionally", ",", "after", "the", "high", "dose", "of", "100", "mg", "/", "kg", "COMPOUND_XXX", "per", "day", ":", "-", "At", "necropsy", ",", "cystic", "dilatation", "of", "the", "mesovarium", "was", "noted", "in", "one", "animal", "(", "suspected", "compound", "-", "related", ")", "." ]	[ "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", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Toxicokinetic evaluations were conducted on plasma samples collected on study days 1 and during week 13 at 5 minutes , 0.5 , 2 , 4 , and 24 hours post dose .	[ "Toxicokinetic", "evaluations", "were", "conducted", "on", "plasma", "samples", "collected", "on", "study", "days", "1", "and", "during", "week", "13", "at", "5", "minutes", ",", "0.5", ",", "2", ",", "4", ",", "and", "24", "hours", "post", "dose", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 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	Uterus , ovaries and mammary glands exhibited vacuolations .	[ "Uterus", ",", "ovaries", "and", "mammary", "glands", "exhibited", "vacuolations", "." ]	[ "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-FINDING", "O" ]	[ 10, 11, 11, 0, 10, 11, 0, 8, 0 ]
NO_PRETOX_REL	A comparison of C max at the different dose levels shows a linear increase with a dose proportionality factor exceeding the dose increase ( TF 2 ) .	[ "A", "comparison", "of", "C", "max", "at", "the", "different", "dose", "levels", "shows", "a", "linear", "increase", "with", "a", "dose", "proportionality", "factor", "exceeding", "the", "dose", "increase", "(", "TF", "2", ")", "." ]	[ "O", "O", "O", "O", "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 overall mean cumulative body weight gain on Day 28 was reduced by 12 % compared with the control females .	[ "The", "overall", "mean", "cumulative", "body", "weight", "gain", "on", "Day", "28", "was", "reduced", "by", "12", "%", "compared", "with", "the", "control", "females", "." ]	[ "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O" ]	[ 0, 0, 0, 0, 2, 6, 6, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 5, 0 ]
NO_PRETOX_REL	Protocol - specified organs were weighed , tissues were collected , processed and microscopically examined .	[ "Protocol", "-", "specified", "organs", "were", "weighed", ",", "tissues", "were", "collected", ",", "processed", "and", "microscopically", "examined", "." ]	[ "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	Although there was no consistent difference in exposure observed between male and female dogs , the apparently greater AUC and Cmax values in females at 45 mg / kg / day , albeit with large variations , taken together with the clinical signs noted primarily in females at 45 mg / kg / day , and body weight and food consumption effects at the same dose , supports the conclusion that there was a greater exposure in females at the high dose .	[ "Although", "there", "was", "no", "consistent", "difference", "in", "exposure", "observed", "between", "male", "and", "female", "dogs", ",", "the", "apparently", "greater", "AUC", "and", "Cmax", "values", "in", "females", "at", "45", "mg", "/", "kg", "/", "day", ",", "albeit", "with", "large", "variations", ",", "taken", "together", "with", "the", "clinical", "signs", "noted", "primarily", "in", "females", "at", "45", "mg", "/", "kg", "/", "day", ",", "and", "body", "weight", "and", "food", "consumption", "effects", "at", "the", "same", "dose", ",", "supports", "the", "conclusion", "that", "there", "was", "a", "greater", "exposure", "in", "females", "at", "the", "high", "dose", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "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", "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", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "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, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0 ]
PRETOX_REL	Findings after the high dose of 150/100 mg / kg COMPOUND_XXX are regarded as signs of general toxicity of the compound .	[ "Findings", "after", "the", "high", "dose", "of", "150/100", "mg", "/", "kg", "COMPOUND_XXX", "are", "regarded", "as", "signs", "of", "general", "toxicity", "of", "the", "compound", "." ]	[ "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O" ]	[ 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 0, 0, 0, 8, 9, 9, 9, 0, 0, 0, 0 ]
PRETOX_REL	Accordingly , body weight gain was decreased by approximately 50 % ( males ) and 70 % ( females ) .	[ "Accordingly", ",", "body", "weight", "gain", "was", "decreased", "by", "approximately", "50", "%", "(", "males", ")", "and", "70", "%", "(", "females", ")", "." ]	[ "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "B-SEX", "O", "O" ]	[ 0, 0, 2, 6, 6, 0, 1, 0, 0, 0, 0, 0, 5, 0, 0, 0, 0, 0, 5, 0, 0 ]
NO_PRETOX_REL	All organ weight changes were observed in both relative and absolute values .	[ "All", "organ", "weight", "changes", "were", "observed", "in", "both", "relative", "and", "absolute", "values", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	These changes were similarly noted from day 3 to day 15 , with the exception of minimal hypertrophy of Paneth cells in the ileal crypts , which was most obvious on day 3 .	[ "These", "changes", "were", "similarly", "noted", "from", "day", "3", "to", "day", "15", ",", "with", "the", "exception", "of", "minimal", "hypertrophy", "of", "Paneth", "cells", "in", "the", "ileal", "crypts", ",", "which", "was", "most", "obvious", "on", "day", "3", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "B-SPECIMEN", "I-SPECIMEN", "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, 8, 0, 10, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Minimal to slight focal and / or macular erythema affecting parts of the application area was evident during several days in two females treated with the reference item , in one male and one female at 100 mg / kg and in two males at 200 mg / kg from weeks 4 to 9 .	[ "Minimal", "to", "slight", "focal", "and", "/", "or", "macular", "erythema", "affecting", "parts", "of", "the", "application", "area", "was", "evident", "during", "several", "days", "in", "two", "females", "treated", "with", "the", "reference", "item", ",", "in", "one", "male", "and", "one", "female", "at", "100", "mg", "/", "kg", "and", "in", "two", "males", "at", "200", "mg", "/", "kg", "from", "weeks", "4", "to", "9", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 5, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 0, 5, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	One female from the high dose group developed emaciation and exsiccosis .	[ "One", "female", "from", "the", "high", "dose", "group", "developed", "emaciation", "and", "exsiccosis", "." ]	[ "O", "B-SEX", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "B-FINDING", "O", "B-FINDING", "O" ]	[ 0, 5, 0, 0, 12, 13, 13, 0, 8, 0, 8, 0 ]
PRETOX_REL	- The effects in the male genital organs were of progressive nature leading to complete loss of spermatogenesis , occurrence of tubular giant cells in the testes , and reduced secretion in the prostate gland with dense , inactive epithelia .	[ "-", "The", "effects", "in", "the", "male", "genital", "organs", "were", "of", "progressive", "nature", "leading", "to", "complete", "loss", "of", "spermatogenesis", ",", "occurrence", "of", "tubular", "giant", "cells", "in", "the", "testes", ",", "and", "reduced", "secretion", "in", "the", "prostate", "gland", "with", "dense", ",", "inactive", "epithelia", "." ]	[ "O", "O", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "B-FINDING", "I-FINDING", "O" ]	[ 0, 0, 0, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 9, 0, 0, 0, 8, 9, 9, 0, 0, 10, 0, 0, 8, 9, 0, 0, 10, 11, 0, 0, 0, 8, 9, 0 ]
NO_PRETOX_REL	COMPOUND_XXX ( hydrochloride , batch no .	[ "COMPOUND_XXX", "(", "hydrochloride", ",", "batch", "no", "." ]	[ "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	After the end of the treatment period , the surviving recovery animals were observed for at least a further 8 weeks to investigate the reversibility of possible treatment related effects .	[ "After", "the", "end", "of", "the", "treatment", "period", ",", "the", "surviving", "recovery", "animals", "were", "observed", "for", "at", "least", "a", "further", "8", "weeks", "to", "investigate", "the", "reversibility", "of", "possible", "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", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The alterations were associated with the appearance of antinucleolar antibodies in the liver .	[ "The", "alterations", "were", "associated", "with", "the", "appearance", "of", "antinucleolar", "antibodies", "in", "the", "liver", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 0 ]
PRETOX_REL	The acute nearly complete necrosis of the liver parenchyma ( red dystrophy ) was responsible for the premature death or of the moribund condition of the female animals .	[ "The", "acute", "nearly", "complete", "necrosis", "of", "the", "liver", "parenchyma", "(", "red", "dystrophy", ")", "was", "responsible", "for", "the", "premature", "death", "or", "of", "the", "moribund", "condition", "of", "the", "female", "animals", "." ]	[ "O", "O", "O", "O", "B-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SEX", "O", "O" ]	[ 0, 0, 0, 0, 8, 0, 0, 10, 11, 0, 8, 9, 0, 0, 0, 0, 0, 8, 9, 0, 0, 0, 8, 9, 0, 0, 5, 0, 0 ]
NO_PRETOX_REL	Transmission electron microscopy was performed on livers from selected animals .	[ "Transmission", "electron", "microscopy", "was", "performed", "on", "livers", "from", "selected", "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	A dose - dependent , statistically significant inhibition of the DAO activity in the jejunal mucosa was evident in both treated groups at all 8 time points .	[ "A", "dose", "-", "dependent", ",", "statistically", "significant", "inhibition", "of", "the", "DAO", "activity", "in", "the", "jejunal", "mucosa", "was", "evident", "in", "both", "treated", "groups", "at", "all", "8", "time", "points", "." ]	[ "O", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0, 0, 10, 11, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Five groups of 6 male and 6 female rats for the toxicity study and five groups of 10 male and 10 female rats for the toxicokinetic study were given 0 , 30 , 100 , 300 or 600 mg / kg / day for five days .	[ "Five", "groups", "of", "6", "male", "and", "6", "female", "rats", "for", "the", "toxicity", "study", "and", "five", "groups", "of", "10", "male", "and", "10", "female", "rats", "for", "the", "toxicokinetic", "study", "were", "given", "0", ",", "30", ",", "100", ",", "300", "or", "600", "mg", "/", "kg", "/", "day", "for", "five", "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", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "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, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0 ]
PRETOX_REL	The degree of inhibition was similar during the course of the last treatment day at 600 mg / kg , but showed a variation at 60 mg / kg / day with a higher enzyme inhibition during the night .	[ "The", "degree", "of", "inhibition", "was", "similar", "during", "the", "course", "of", "the", "last", "treatment", "day", "at", "600", "mg", "/", "kg", ",", "but", "showed", "a", "variation", "at", "60", "mg", "/", "kg", "/", "day", "with", "a", "higher", "enzyme", "inhibition", "during", "the", "night", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-MANIFESTATION_FINDING", "B-FINDING", "I-FINDING", "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, 3, 4, 4, 4, 4, 4, 0, 0, 1, 8, 9, 0, 0, 0, 0 ]
NO_PRETOX_REL	Ophthalmoscopic assessments were undertaken on all animals during pretrial and on Control and High dose animals after approximately 26 weeks of dosing .	[ "Ophthalmoscopic", "assessments", "were", "undertaken", "on", "all", "animals", "during", "pretrial", "and", "on", "Control", "and", "High", "dose", "animals", "after", "approximately", "26", "weeks", "of", "dosing", "." ]	[ "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", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	The body weight loss noted at 1.0 mg / kg / occasion correlated with an observed decrease in food consumption .	[ "The", "body", "weight", "loss", "noted", "at", "1.0", "mg", "/", "kg", "/", "occasion", "correlated", "with", "an", "observed", "decrease", "in", "food", "consumption", "." ]	[ "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O" ]	[ 0, 2, 6, 1, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 1, 0, 2, 6, 0 ]
PRETOX_REL	Summary of results The following treatment - related finding were observed at the low dose of 0.2 mg / kg COMPOUND_XXX and higher : - hepatocellular hypertrophy in the liver with increased incidence and severity ; - acinar hypertrophy of the parotid gland .	[ "Summary", "of", "results", "The", "following", "treatment", "-", "related", "finding", "were", "observed", "at", "the", "low", "dose", "of", "0.2", "mg", "/", "kg", "COMPOUND_XXX", "and", "higher", ":", "-", "hepatocellular", "hypertrophy", "in", "the", "liver", "with", "increased", "incidence", "and", "severity", ";", "-", "acinar", "hypertrophy", "of", "the", "parotid", "gland", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 15, 16, 0, 3, 4, 4, 4, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 0, 1, 0, 0, 0, 0, 0, 8, 9, 0, 0, 10, 11, 0 ]
NO_PRETOX_REL	The tables give the counts of ASAT , ALAT , APh , GLDH , GGT , LDH , CK , GLUCOSE , CHOL , TRIGL , CREA , UREA , BILI - t , PROT , ALBUMIN , Na , K , Ca , Cl , P , Fe , Mg , T3 , 14 , and from the liver tissue the parameters N - DEM , O - DEM , P 450 , and TRIGL ( for the use of abbreviations see List of methods in the appendix of the report ) 22 COMPOUND_XXX T 1071175 eS ETT As can be seen from the tables , no changes were detected up to and including group Ul .	[ "The", "tables", "give", "the", "counts", "of", "ASAT", ",", "ALAT", ",", "APh", ",", "GLDH", ",", "GGT", ",", "LDH", ",", "CK", ",", "GLUCOSE", ",", "CHOL", ",", "TRIGL", ",", "CREA", ",", "UREA", ",", "BILI", "-", "t", ",", "PROT", ",", "ALBUMIN", ",", "Na", ",", "K", ",", "Ca", ",", "Cl", ",", "P", ",", "Fe", ",", "Mg", ",", "T3", ",", "14", ",", "and", "from", "the", "liver", "tissue", "the", "parameters", "N", "-", "DEM", ",", "O", "-", "DEM", ",", "P", "450", ",", "and", "TRIGL", "(", "for", "the", "use", "of", "abbreviations", "see", "List", "of", "methods", "in", "the", "appendix", "of", "the", "report", ")", "22", "COMPOUND_XXX", "T", "1071175", "eS", "ETT", "As", "can", "be", "seen", "from", "the", "tables", ",", "no", "changes", "were", "detected", "up", "to", "and", "including", "group", "Ul", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0 ]
NO_PRETOX_REL	Exposures were generally higher in females than in males , especially in the low dose group .	[ "Exposures", "were", "generally", "higher", "in", "females", "than", "in", "males", ",", "especially", "in", "the", "low", "dose", "group", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 0 ]
PRETOX_REL	At this same dose , animals exhibited skin anomalies such as desquamations traducing as hyperplasia and hyperkeratosis histologically , indurations and increased vulnerability .	[ "At", "this", "same", "dose", ",", "animals", "exhibited", "skin", "anomalies", "such", "as", "desquamations", "traducing", "as", "hyperplasia", "and", "hyperkeratosis", "histologically", ",", "indurations", "and", "increased", "vulnerability", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "B-SPECIMEN", "O", "O", "O", "B-FINDING", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "B-FINDING", "O", "B-FINDING", "I-FINDING", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 10, 0, 0, 0, 8, 0, 0, 8, 9, 9, 0, 0, 8, 0, 8, 9, 0 ]
NO_PRETOX_REL	Conclusion No NOEL could be established in this study .	[ "Conclusion", "No", "NOEL", "could", "be", "established", "in", "this", "study", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Animals were dosed for 4 cycles , receiving doses of 0 ( control ) , 0.06 , 0.2 and 0.6 mg / kg per day at a dose volume of 2 mL / kg .	[ "Animals", "were", "dosed", "for", "4", "cycles", ",", "receiving", "doses", "of", "0", "(", "control", ")", ",", "0.06", ",", "0.2", "and", "0.6", "mg", "/", "kg", "per", "day", "at", "a", "dose", "volume", "of", "2", "mL", "/", "kg", "." ]	[ "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", "O" ]	[ 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, 0 ]
NO_PRETOX_REL	In Weeks 1 , 12 , 25 , 38 and 51 heparinized whole blood was collected from 5 animals / sex / group for determination of blood drug levels .	[ "In", "Weeks", "1", ",", "12", ",", "25", ",", "38", "and", "51", "heparinized", "whole", "blood", "was", "collected", "from", "5", "animals", "/", "sex", "/", "group", "for", "determination", "of", "blood", "drug", "levels", "." ]	[ "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", "I-GROUP", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 13, 13, 13, 13, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	- decrease in heart rate was noted in male animals on day 8 .	[ "-", "decrease", "in", "heart", "rate", "was", "noted", "in", "male", "animals", "on", "day", "8", "." ]	[ "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "B-SEX", "O", "O", "O", "O", "O" ]	[ 0, 1, 0, 2, 6, 0, 0, 0, 5, 0, 0, 0, 0, 0 ]
PRETOX_REL	Haemorrhages and infarcts were found in a large number of organs .	[ "Haemorrhages", "and", "infarcts", "were", "found", "in", "a", "large", "number", "of", "organs", "." ]	[ "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	All animals survived the 13 - week dosing period .	[ "All", "animals", "survived", "the", "13", "-", "week", "dosing", "period", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No sex effect was observed except on the first day when measurable levels appeared later in the females than in males .	[ "No", "sex", "effect", "was", "observed", "except", "on", "the", "first", "day", "when", "measurable", "levels", "appeared", "later", "in", "the", "females", "than", "in", "males", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	This study was designed to establish a no toxic effect level , to estimate the toxicokinetic profile , and to estimate the potential for reversal of any toxic effects within a 4 - week recovery phase .	[ "This", "study", "was", "designed", "to", "establish", "a", "no", "toxic", "effect", "level", ",", "to", "estimate", "the", "toxicokinetic", "profile", ",", "and", "to", "estimate", "the", "potential", "for", "reversal", "of", "any", "toxic", "effects", "within", "a", "4", "-", "week", "recovery", "phase", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	When compared to controls the administration of COMPOUND_XXX , daily , for 4 weeks produced the following treatment - related changes .	[ "When", "compared", "to", "controls", "the", "administration", "of", "COMPOUND_XXX", ",", "daily", ",", "for", "4", "weeks", "produced", "the", "following", "treatment", "-", "related", "changes", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	One high - dose recovery animal was terminated prior to the end of study in response to a condition suspected to be due to an error in dosing .	[ "One", "high", "-", "dose", "recovery", "animal", "was", "terminated", "prior", "to", "the", "end", "of", "study", "in", "response", "to", "a", "condition", "suspected", "to", "be", "due", "to", "an", "error", "in", "dosing", "." ]	[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "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, 15, 16, 16, 0, 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	However , systemic exposure , as indicated by maximum concentrations and a limited number of samples above the lower limit of quantification ( LLOQ , 0.1 ng / mL ) , increased with the dose and with the time period of treatment .	[ "However", ",", "systemic", "exposure", ",", "as", "indicated", "by", "maximum", "concentrations", "and", "a", "limited", "number", "of", "samples", "above", "the", "lower", "limit", "of", "quantification", "(", "LLOQ", ",", "0.1", "ng", "/", "mL", ")", ",", "increased", "with", "the", "dose", "and", "with", "the", "time", "period", "of", "treatment", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Blood was collected at various time points for toxicokinetic analysis on days 1 and 15 .	[ "Blood", "was", "collected", "at", "various", "time", "points", "for", "toxicokinetic", "analysis", "on", "days", "1", "and", "15", "." ]	[ "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	Theses dermal findings are deemed related to treatment with the test substance .	[ "Theses", "dermal", "findings", "are", "deemed", "related", "to", "treatment", "with", "the", "test", "substance", "." ]	[ "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	Water consumption showed no treatment - related changes in males at any dose level compared to control .	[ "Water", "consumption", "showed", "no", "treatment", "-", "related", "changes", "in", "males", "at", "any", "dose", "level", "compared", "to", "control", "." ]	[ "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	Three males and one female receiving 1.5 / 1.0 mg / kg / occasion were noted as being thin in appearance from Week 7 of the study onwards .	[ "Three", "males", "and", "one", "female", "receiving", "1.5", "/", "1.0", "mg", "/", "kg", "/", "occasion", "were", "noted", "as", "being", "thin", "in", "appearance", "from", "Week", "7", "of", "the", "study", "onwards", "." ]	[ "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The degree of thickening was dose - dependant up to 1000 mg / kg / day , when a plateau was reached .	[ "The", "degree", "of", "thickening", "was", "dose", "-", "dependant", "up", "to", "1000", "mg", "/", "kg", "/", "day", ",", "when", "a", "plateau", "was", "reached", "." ]	[ "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" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The lists of individual data are given in Appendix 2 .	[ "The", "lists", "of", "individual", "data", "are", "given", "in", "Appendix", "2", "." ]	[ "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	The purpose of this study was to establish the toxicologic effects of COMPOUND_XXX , a protein - tyrosine kinase inhibitor , when administered to rats for at least 26 weeks .	[ "The", "purpose", "of", "this", "study", "was", "to", "establish", "the", "toxicologic", "effects", "of", "COMPOUND_XXX", ",", "a", "protein", "-", "tyrosine", "kinase", "inhibitor", ",", "when", "administered", "to", "rats", "for", "at", "least", "26", "weeks", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	No test article related microscopic findings were noted in the animals that were dosed twice weekly .	[ "No", "test", "article", "related", "microscopic", "findings", "were", "noted", "in", "the", "animals", "that", "were", "dosed", "twice", "weekly", "." ]	[ "O", "O", "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, 3, 4, 4, 0 ]
NO_PRETOX_REL	XXXX ) and Placebo to COMPOUND_XXX ( patches , batch no .	[ "XXXX", ")", "and", "Placebo", "to", "COMPOUND_XXX", "(", "patches", ",", "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	III ) , resp .	[ "III", ")", ",", "resp", "." ]	[ "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The rats received daily doses of 0 ( CMC - vehicle control ) , 0 ( distilled water control ) , 10 , 40 , 180 , and 800 of Ro mg / kg / day 24-7429/002 at a constant volume of 5 ml / kg / day .	[ "The", "rats", "received", "daily", "doses", "of", "0", "(", "CMC", "-", "vehicle", "control", ")", ",", "0", "(", "distilled", "water", "control", ")", ",", "10", ",", "40", ",", "180", ",", "and", "800", "of", "Ro", "mg", "/", "kg", "/", "day", "24-7429/002", "at", "a", "constant", "volume", "of", "5", "ml", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "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, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Minimal to moderate liver alterations were present in both treated groups with substantial individual variations in occurrence and severity .	[ "Minimal", "to", "moderate", "liver", "alterations", "were", "present", "in", "both", "treated", "groups", "with", "substantial", "individual", "variations", "in", "occurrence", "and", "severity", "." ]	[ "B-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "B-FINDING", "I-FINDING", "O", "O", "O", "B-GROUP", "I-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 1, 14, 14, 8, 9, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Female animals appeared to be exposed to higher levels of COMPOUND_XXX compared to males .	[ "Female", "animals", "appeared", "to", "be", "exposed", "to", "higher", "levels", "of", "COMPOUND_XXX", "compared", "to", "males", "." ]	[ "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 ]
PRETOX_REL	Total food consumption was slightly low for males at 50 mg / kg / day and for males and females during treatment at 75 mg / kg / day .	[ "Total", "food", "consumption", "was", "slightly", "low", "for", "males", "at", "50", "mg", "/", "kg", "/", "day", "and", "for", "males", "and", "females", "during", "treatment", "at", "75", "mg", "/", "kg", "/", "day", "." ]	[ "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-MANIFESTATION_FINDING", "I-MANIFESTATION_FINDING", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "I-SEX", "I-SEX", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 2, 6, 0, 1, 14, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 0, 5, 7, 7, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	Systemic exposure to COMPOUND_XXX was generally dose proportional .	[ "Systemic", "exposure", "to", "COMPOUND_XXX", "was", "generally", "dose", "proportional", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Decedent : On study day 13 , one satellite female at 30 mg / kg / day was sacrificed due to animal welfare reasons and selected for necropsy .	[ "Decedent", ":", "On", "study", "day", "13", ",", "one", "satellite", "female", "at", "30", "mg", "/", "kg", "/", "day", "was", "sacrificed", "due", "to", "animal", "welfare", "reasons", "and", "selected", "for", "necropsy", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Analogously , hyperinsulinemia as a consequence of an insulin - secreting tumor has also been associated with development of peripheral nerve pathology [ 6 ] .	[ "Analogously", ",", "hyperinsulinemia", "as", "a", "consequence", "of", "an", "insulin", "-", "secreting", "tumor", "has", "also", "been", "associated", "with", "development", "of", "peripheral", "nerve", "pathology", "[", "6", "]", "." ]	[ "O", "O", "B-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, 0, 8, 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	None of the observed effects apart from the vomiting is regarded as adverse .	[ "None", "of", "the", "observed", "effects", "apart", "from", "the", "vomiting", "is", "regarded", "as", "adverse", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 8, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	individual body weights and food consumption were recorded weekly .	[ "individual", "body", "weights", "and", "food", "consumption", "were", "recorded", "weekly", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Food consumption was unchanged during the treatment period in both genders , and in females during the recovery period .	[ "Food", "consumption", "was", "unchanged", "during", "the", "treatment", "period", "in", "both", "genders", ",", "and", "in", "females", "during", "the", "recovery", "period", "." ]	[ "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	XXXXX .	[ "XXXXX", "." ]	[ "O", "O" ]	[ 0, 0 ]
NO_PRETOX_REL	The reversibility from the effects was also assessed during a 2 - week recovery period .	[ "The", "reversibility", "from", "the", "effects", "was", "also", "assessed", "during", "a", "2", "-", "week", "recovery", "period", "." ]	[ "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 ]
PRETOX_REL	Only very slight erythema was noted in animals dosed twice weekly .	[ "Only", "very", "slight", "erythema", "was", "noted", "in", "animals", "dosed", "twice", "weekly", "." ]	[ "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "O" ]	[ 0, 0, 8, 9, 0, 0, 0, 0, 3, 4, 4, 0 ]
NO_PRETOX_REL	Organ Weights The comparison of mean values of absolute and relative organ weights of the test article treated animals to the corresponding values of the control animals and a statistical analysis by using the DUNNETT test showed a compound - related difference between the test article treated animals and the controls ( see Text Tables in the appendix Several other partly statistically significant differences in group mean absolute and / or relative organ weights were considered incidental and not compound - related as they were slight , not dose - related , observed only in one sex and / or unaccompanied by correlated morphologic findings .	[ "Organ", "Weights", "The", "comparison", "of", "mean", "values", "of", "absolute", "and", "relative", "organ", "weights", "of", "the", "test", "article", "treated", "animals", "to", "the", "corresponding", "values", "of", "the", "control", "animals", "and", "a", "statistical", "analysis", "by", "using", "the", "DUNNETT", "test", "showed", "a", "compound", "-", "related", "difference", "between", "the", "test", "article", "treated", "animals", "and", "the", "controls", "(", "see", "Text", "Tables", "in", "the", "appendix", "Several", "other", "partly", "statistically", "significant", "differences", "in", "group", "mean", "absolute", "and", "/", "or", "relative", "organ", "weights", "were", "considered", "incidental", "and", "not", "compound", "-", "related", "as", "they", "were", "slight", ",", "not", "dose", "-", "related", ",", "observed", "only", "in", "one", "sex", "and", "/", "or", "unaccompanied", "by", "correlated", "morphologic", "findings", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The No Observed Effect Level in this study was 50 ppm in both sexes , equating approximately to 3.5 mg / kg / day in males and 4.1 mg / kg / day in females .	[ "The", "No", "Observed", "Effect", "Level", "in", "this", "study", "was", "50", "ppm", "in", "both", "sexes", ",", "equating", "approximately", "to", "3.5", "mg", "/", "kg", "/", "day", "in", "males", "and", "4.1", "mg", "/", "kg", "/", "day", "in", "females", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "O", "O", "O", "O", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 0, 0, 0, 0, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0 ]
PRETOX_REL	At necropsy all group III ( 30/60 mg / kg ) - males showed a reddish discoloration of the mesenteric lymph nodes .	[ "At", "necropsy", "all", "group", "III", "(", "30/60", "mg", "/", "kg", ")", "-", "males", "showed", "a", "reddish", "discoloration", "of", "the", "mesenteric", "lymph", "nodes", "." ]	[ "O", "O", "O", "B-GROUP", "I-GROUP", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "B-SEX", "O", "O", "B-FINDING", "I-FINDING", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 12, 13, 0, 3, 4, 4, 4, 0, 0, 5, 0, 0, 8, 9, 0, 0, 10, 11, 11, 0 ]
NO_PRETOX_REL	It is deemed related to treatment with the test substance .	[ "It", "is", "deemed", "related", "to", "treatment", "with", "the", "test", "substance", "." ]	[ "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	The details can be taken from the pathology report in the appendix of the report .	[ "The", "details", "can", "be", "taken", "from", "the", "pathology", "report", "in", "the", "appendix", "of", "the", "report", "." ]	[ "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 ]
PRETOX_REL	In females , mean absolute liver weight , liver to body weight and liver to brain weight ratios were increased by 20 % , 24 % and 18 % , respectively .	[ "In", "females", ",", "mean", "absolute", "liver", "weight", ",", "liver", "to", "body", "weight", "and", "liver", "to", "brain", "weight", "ratios", "were", "increased", "by", "20", "%", ",", "24", "%", "and", "18", "%", ",", "respectively", "." ]	[ "O", "B-SEX", "O", "O", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "B-SPECIMEN", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 5, 0, 0, 0, 10, 2, 0, 10, 0, 2, 6, 0, 10, 0, 10, 2, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	There were no consistent differences in exposure to COMPOUND_XXX or YYYYY between males and females .	[ "There", "were", "no", "consistent", "differences", "in", "exposure", "to", "COMPOUND_XXX", "or", "YYYYY", "between", "males", "and", "females", "." ]	[ "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	All organ weight changes were reversible following the recovery period .	[ "All", "organ", "weight", "changes", "were", "reversible", "following", "the", "recovery", "period", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Laboratory diagnostics : - decrease in index of erythropoiesis / granulopoiesis , decrease in the number of erythropoietic cells and an increase in the number of neutrophilic cells was observed in the bone marrow examination in male animals ( interim sacrifice on day 10 ) .	[ "Laboratory", "diagnostics", ":", "-", "decrease", "in", "index", "of", "erythropoiesis", "/", "granulopoiesis", ",", "decrease", "in", "the", "number", "of", "erythropoietic", "cells", "and", "an", "increase", "in", "the", "number", "of", "neutrophilic", "cells", "was", "observed", "in", "the", "bone", "marrow", "examination", "in", "male", "animals", "(", "interim", "sacrifice", "on", "day", "10", ")", "." ]	[ "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "B-FINDING", "O", "B-FINDING", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "B-SEX", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 1, 0, 0, 0, 8, 0, 8, 0, 1, 0, 0, 0, 0, 2, 6, 0, 0, 1, 0, 0, 0, 0, 2, 6, 0, 0, 0, 0, 10, 11, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In all high - dose rats , the ear pinnae , xiphoid cartilages , and skin were discolored yellow .	[ "In", "all", "high", "-", "dose", "rats", ",", "the", "ear", "pinnae", ",", "xiphoid", "cartilages", ",", "and", "skin", "were", "discolored", "yellow", "." ]	[ "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "B-SPECIMEN", "O", "B-FINDING", "I-FINDING", "O" ]	[ 0, 0, 15, 16, 16, 0, 0, 0, 10, 11, 0, 10, 11, 0, 0, 10, 0, 8, 9, 0 ]
PRETOX_REL	In conclusion , oral administration of COMPOUND_XXX by gavage to rats for 4 weeks resulted in test article - related statistically significant decreases in mean body weight and mean body weight gain in males at 60 mg / kg / day , organ weight changes in both sexes at 60 mg / kg / day and renal changes in males at doses ≥ 6 mg / kg / day .	[ "In", "conclusion", ",", "oral", "administration", "of", "COMPOUND_XXX", "by", "gavage", "to", "rats", "for", "4", "weeks", "resulted", "in", "test", "article", "-", "related", "statistically", "significant", "decreases", "in", "mean", "body", "weight", "and", "mean", "body", "weight", "gain", "in", "males", "at", "60", "mg", "/", "kg", "/", "day", ",", "organ", "weight", "changes", "in", "both", "sexes", "at", "60", "mg", "/", "kg", "/", "day", "and", "renal", "changes", "in", "males", "at", "doses", "≥", "6", "mg", "/", "kg", "/", "day", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "B-MANIFESTATION_FINDING", "O", "B-SEX", "I-SEX", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "B-FINDING", "I-FINDING", "O", "B-SEX", "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, 0, 0, 0, 0, 0, 1, 0, 0, 2, 6, 0, 0, 2, 6, 6, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 10, 2, 1, 0, 5, 7, 0, 3, 4, 4, 4, 4, 4, 0, 8, 9, 0, 5, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]
PRETOX_REL	Otherwise only background findings common to Füllinsdorfer Albino - rats were seen .	[ "Otherwise", "only", "background", "findings", "common", "to", "Füllinsdorfer", "Albino", "-", "rats", "were", "seen", "." ]	[ "O", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 8, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The relevance of these findings remains unclear .	[ "The", "relevance", "of", "these", "findings", "remains", "unclear", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	Microscopic examination of the joints revealed growth plate thickening , indicating pharmacological activity , without any adverse changes .	[ "Microscopic", "examination", "of", "the", "joints", "revealed", "growth", "plate", "thickening", ",", "indicating", "pharmacological", "activity", ",", "without", "any", "adverse", "changes", "." ]	[ "O", "O", "O", "O", "B-SPECIMEN", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 10, 0, 8, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	( ~ ~ Microscopic investigation of the urinary sediments involving differentiation into bacteria , epithelial cells , leucocytes , erythrocytes and amorphous salts did not bring to light any notable quantitative or qualitative differences between the control groups and the treatment groups up to and including group Ill as regards the composition of the sediments .	[ "(", "~", "~", "Microscopic", "investigation", "of", "the", "urinary", "sediments", "involving", "differentiation", "into", "bacteria", ",", "epithelial", "cells", ",", "leucocytes", ",", "erythrocytes", "and", "amorphous", "salts", "did", "not", "bring", "to", "light", "any", "notable", "quantitative", "or", "qualitative", "differences", "between", "the", "control", "groups", "and", "the", "treatment", "groups", "up", "to", "and", "including", "group", "Ill", "as", "regards", "the", "composition", "of", "the", "sediments", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "B-GROUP", "I-GROUP", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 13, 0, 0, 12, 13, 0, 0, 0, 0, 12, 13, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	There were no COMPOUND_XXX - related changes at 40 mg / kg / day .	[ "There", "were", "no", "COMPOUND_XXX", "-", "related", "changes", "at", "40", "mg", "/", "kg", "/", "day", "." ]	[ "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, 3, 4, 4, 4, 4, 4, 0 ]
NO_PRETOX_REL	The following investigations were performed : mortality , clinical signs , body weight , urinalysis , toxicokinetic investigations , necropsy , macroscopic and microscopic examinations ( including immunohistochemistry ) , and pharmacogenomic investigations .	[ "The", "following", "investigations", "were", "performed", ":", "mortality", ",", "clinical", "signs", ",", "body", "weight", ",", "urinalysis", ",", "toxicokinetic", "investigations", ",", "necropsy", ",", "macroscopic", "and", "microscopic", "examinations", "(", "including", "immunohistochemistry", ")", ",", "and", "pharmacogenomic", "investigations", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	The study was designed to establish a no - observed - adverse - effect level ( NOAEL ) , to estimate the toxicokinetic profile , and to estimate the potential for reversal of any toxic effects within a 4 - week postdosing phase .	[ "The", "study", "was", "designed", "to", "establish", "a", "no", "-", "observed", "-", "adverse", "-", "effect", "level", "(", "NOAEL", ")", ",", "to", "estimate", "the", "toxicokinetic", "profile", ",", "and", "to", "estimate", "the", "potential", "for", "reversal", "of", "any", "toxic", "effects", "within", "a", "4", "-", "week", "postdosing", "phase", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	COMPOUND_XXX - related reductions in neutrophil , lymphocyte , monocyte and eosinophil counts at 30 and 75 mg / kg were associated with myeloid series changes ( maturation arrest ) observed during bone marrow cytological evaluation .	[ "COMPOUND_XXX", "-", "related", "reductions", "in", "neutrophil", ",", "lymphocyte", ",", "monocyte", "and", "eosinophil", "counts", "at", "30", "and", "75", "mg", "/", "kg", "were", "associated", "with", "myeloid", "series", "changes", "(", "maturation", "arrest", ")", "observed", "during", "bone", "marrow", "cytological", "evaluation", "." ]	[ "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "O", "B-FINDING", "I-FINDING", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O" ]	[ 0, 0, 0, 1, 0, 2, 0, 2, 0, 2, 0, 2, 6, 0, 3, 4, 4, 4, 4, 4, 0, 0, 0, 8, 9, 9, 0, 8, 9, 0, 0, 0, 10, 11, 0, 0, 0 ]
NO_PRETOX_REL	No treatment - related effects on hematological parameters , organ weights , macroscopic or microscopic findings were observed at either 100 or 300 mg / kg / day .	[ "No", "treatment", "-", "related", "effects", "on", "hematological", "parameters", ",", "organ", "weights", ",", "macroscopic", "or", "microscopic", "findings", "were", "observed", "at", "either", "100", "or", "300", "mg", "/", "kg", "/", "day", "." ]	[ "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", "O" ]	[ 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, 0 ]
PRETOX_REL	Adrenal cortical hypertrophy noted at the high dose as well as reductions in thymus and spleen weights were attributed to a stress - like response to hypoglycemia .	[ "Adrenal", "cortical", "hypertrophy", "noted", "at", "the", "high", "dose", "as", "well", "as", "reductions", "in", "thymus", "and", "spleen", "weights", "were", "attributed", "to", "a", "stress", "-", "like", "response", "to", "hypoglycemia", "." ]	[ "B-FINDING", "I-FINDING", "I-FINDING", "O", "O", "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "B-STUDY_TESTCD", "O", "O", "O", "O", "B-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "I-FINDING", "O" ]	[ 8, 9, 9, 0, 0, 0, 15, 16, 0, 0, 0, 1, 0, 10, 0, 10, 2, 0, 0, 0, 0, 8, 9, 9, 9, 9, 9, 0 ]
NO_PRETOX_REL	a. Clinical observations The table for the evaluation of the nutritional state can be found in the appendix of the report .	[ "a.", "Clinical", "observations", "The", "table", "for", "the", "evaluation", "of", "the", "nutritional", "state", "can", "be", "found", "in", "the", "appendix", "of", "the", "report", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	Blood samples for hematology and clinical chemistry were collected at pretest , and on day 14 .	[ "Blood", "samples", "for", "hematology", "and", "clinical", "chemistry", "were", "collected", "at", "pretest", ",", "and", "on", "day", "14", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
PRETOX_REL	In histopathology treatment related findings were observed in the hemolymphatic system , gastrointestinal tract , female reproductive tract , kidney , bone , salivary glands , lung , trachea and thyroid gland .	[ "In", "histopathology", "treatment", "related", "findings", "were", "observed", "in", "the", "hemolymphatic", "system", ",", "gastrointestinal", "tract", ",", "female", "reproductive", "tract", ",", "kidney", ",", "bone", ",", "salivary", "glands", ",", "lung", ",", "trachea", "and", "thyroid", "gland", "." ]	[ "O", "O", "O", "O", "B-FINDING", "O", "O", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "B-SPECIMEN", "O", "B-SPECIMEN", "I-SPECIMEN", "O" ]	[ 0, 0, 0, 0, 8, 0, 0, 0, 0, 10, 11, 0, 10, 11, 0, 10, 11, 11, 0, 10, 0, 10, 0, 10, 11, 0, 10, 11, 10, 0, 10, 11, 0 ]
PRETOX_REL	8 ) Increased weight of the salivary glands was noted in females in the 50 mg / kg group .	[ "8", ")", "Increased", "weight", "of", "the", "salivary", "glands", "was", "noted", "in", "females", "in", "the", "50", "mg", "/", "kg", "group", "." ]	[ "O", "O", "B-MANIFESTATION_FINDING", "B-STUDY_TESTCD", "O", "O", "B-SPECIMEN", "I-SPECIMEN", "O", "O", "O", "B-SEX", "O", "O", "B-DOSE", "I-DOSE", "I-DOSE", "I-DOSE", "O", "O" ]	[ 0, 0, 1, 2, 0, 0, 10, 11, 0, 0, 0, 5, 0, 0, 3, 4, 4, 4, 0, 0 ]
NO_PRETOX_REL	The reversibility of treatment - related effects was assessed following a four - week recovery period .	[ "The", "reversibility", "of", "treatment", "-", "related", "effects", "was", "assessed", "following", "a", "four", "-", "week", "recovery", "period", "." ]	[ "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 ]
NO_PRETOX_REL	Toxicokinetic analysis revealed a dose - dependent systemic exposure .	[ "Toxicokinetic", "analysis", "revealed", "a", "dose", "-", "dependent", "systemic", "exposure", "." ]	[ "O", "O", "O", "O", "O", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
NO_PRETOX_REL	All findings showed a tendency to normalization by the end of the recovery period .	[ "All", "findings", "showed", "a", "tendency", "to", "normalization", "by", "the", "end", "of", "the", "recovery", "period", "." ]	[ "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 ]
PRETOX_REL	The number of neutrophilic granulocytes was slightly increased ( statistically significant ) , whereas the absolute basophil number was slightly decreased ( statistically significant ) .	[ "The", "number", "of", "neutrophilic", "granulocytes", "was", "slightly", "increased", "(", "statistically", "significant", ")", ",", "whereas", "the", "absolute", "basophil", "number", "was", "slightly", "decreased", "(", "statistically", "significant", ")", "." ]	[ "O", "O", "O", "B-STUDY_TESTCD", "I-STUDY_TESTCD", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O", "O", "O", "O", "B-STUDY_TESTCD", "O", "O", "O", "B-MANIFESTATION_FINDING", "O", "O", "O", "O", "O" ]	[ 0, 0, 0, 2, 6, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 2, 0, 0, 0, 1, 0, 0, 0, 0, 0 ]

PRETOX_REL

At 3 mg / kg , a pronounced decrease of terminal body weight and of absolute and relative thymus and spleen weights were found in one male .

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PRETOX_REL

The main finding was atrophy of epithelium in various organs , often accompanied by inflammation .

[ "The", "main", "finding", "was", "atrophy", "of", "epithelium", "in", "various", "organs", ",", "often", "accompanied", "by", "inflammation", "." ]

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NO_PRETOX_REL

_ The evaluation of blood pressure and of heart rates ( for individual and mean values see â € ™ appendix of the report ) showed no adverse effects up to and including group ltl .

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NO_PRETOX_REL

No relevant changes were found in females .

[ "No", "relevant", "changes", "were", "found", "in", "females", "." ]

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

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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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PRETOX_REL

Increases in aspartate aminotransferase were present at doses of 1.0 mg / kg / occasion but lacked any microscopic correlate .

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NO_PRETOX_REL

There were no test article - related effects on clinical pathology parameters ( hematology , serum chemistry or urinalysis ) .

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PRETOX_REL

Peripheral neuropathy has been observed in rats subjected to a continuous 72 hour insulin infusion in which glucose levels of approximately 2.5 mM ( 45 mg / dl ) were sustained [ 5 ] .

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PRETOX_REL

Two group III ( 30/60 mg / kg ) - males showed pigment deposition , and one group III ( 30/60 mg / kg ) - male a small area of acute myocardial necrosis .

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PRETOX_REL

Additionally , after the high dose of 100 mg / kg COMPOUND_XXX per day : - At necropsy , cystic dilatation of the mesovarium was noted in one animal ( suspected compound - related ) .

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NO_PRETOX_REL

Toxicokinetic evaluations were conducted on plasma samples collected on study days 1 and during week 13 at 5 minutes , 0.5 , 2 , 4 , and 24 hours post dose .

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PRETOX_REL

Uterus , ovaries and mammary glands exhibited vacuolations .

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NO_PRETOX_REL

A comparison of C max at the different dose levels shows a linear increase with a dose proportionality factor exceeding the dose increase ( TF 2 ) .

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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 overall mean cumulative body weight gain on Day 28 was reduced by 12 % compared with the control females .

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NO_PRETOX_REL

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

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[ "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

Although there was no consistent difference in exposure observed between male and female dogs , the apparently greater AUC and Cmax values in females at 45 mg / kg / day , albeit with large variations , taken together with the clinical signs noted primarily in females at 45 mg / kg / day , and body weight and food consumption effects at the same dose , supports the conclusion that there was a greater exposure in females at the high dose .

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PRETOX_REL

Findings after the high dose of 150/100 mg / kg COMPOUND_XXX are regarded as signs of general toxicity of the compound .

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PRETOX_REL

Accordingly , body weight gain was decreased by approximately 50 % ( males ) and 70 % ( females ) .

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NO_PRETOX_REL

All organ weight changes were observed in both relative and absolute values .

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

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

PRETOX_REL

These changes were similarly noted from day 3 to day 15 , with the exception of minimal hypertrophy of Paneth cells in the ileal crypts , which was most obvious on day 3 .

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PRETOX_REL

Minimal to slight focal and / or macular erythema affecting parts of the application area was evident during several days in two females treated with the reference item , in one male and one female at 100 mg / kg and in two males at 200 mg / kg from weeks 4 to 9 .

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PRETOX_REL

One female from the high dose group developed emaciation and exsiccosis .

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

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

PRETOX_REL

- The effects in the male genital organs were of progressive nature leading to complete loss of spermatogenesis , occurrence of tubular giant cells in the testes , and reduced secretion in the prostate gland with dense , inactive epithelia .

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NO_PRETOX_REL

COMPOUND_XXX ( hydrochloride , batch no .

[ "COMPOUND_XXX", "(", "hydrochloride", ",", "batch", "no", "." ]

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

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

NO_PRETOX_REL

After the end of the treatment period , the surviving recovery animals were observed for at least a further 8 weeks to investigate the reversibility of possible treatment related effects .

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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", "O" ]

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PRETOX_REL

The alterations were associated with the appearance of antinucleolar antibodies in the liver .

[ "The", "alterations", "were", "associated", "with", "the", "appearance", "of", "antinucleolar", "antibodies", "in", "the", "liver", "." ]

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

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

PRETOX_REL

The acute nearly complete necrosis of the liver parenchyma ( red dystrophy ) was responsible for the premature death or of the moribund condition of the female animals .

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NO_PRETOX_REL

Transmission electron microscopy was performed on livers from selected animals .

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

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

PRETOX_REL

A dose - dependent , statistically significant inhibition of the DAO activity in the jejunal mucosa was evident in both treated groups at all 8 time points .

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NO_PRETOX_REL

Five groups of 6 male and 6 female rats for the toxicity study and five groups of 10 male and 10 female rats for the toxicokinetic study were given 0 , 30 , 100 , 300 or 600 mg / kg / day for five days .

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PRETOX_REL

The degree of inhibition was similar during the course of the last treatment day at 600 mg / kg , but showed a variation at 60 mg / kg / day with a higher enzyme inhibition during the night .

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NO_PRETOX_REL

Ophthalmoscopic assessments were undertaken on all animals during pretrial and on Control and High dose animals after approximately 26 weeks of dosing .

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

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PRETOX_REL

The body weight loss noted at 1.0 mg / kg / occasion correlated with an observed decrease in food consumption .

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PRETOX_REL

Summary of results The following treatment - related finding were observed at the low dose of 0.2 mg / kg COMPOUND_XXX and higher : - hepatocellular hypertrophy in the liver with increased incidence and severity ; - acinar hypertrophy of the parotid gland .

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NO_PRETOX_REL

The tables give the counts of ASAT , ALAT , APh , GLDH , GGT , LDH , CK , GLUCOSE , CHOL , TRIGL , CREA , UREA , BILI - t , PROT , ALBUMIN , Na , K , Ca , Cl , P , Fe , Mg , T3 , 14 , and from the liver tissue the parameters N - DEM , O - DEM , P 450 , and TRIGL ( for the use of abbreviations see List of methods in the appendix of the report ) 22 COMPOUND_XXX T 1071175 eS ETT As can be seen from the tables , no changes were detected up to and including group Ul .

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NO_PRETOX_REL

Exposures were generally higher in females than in males , especially in the low dose group .

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

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

PRETOX_REL

At this same dose , animals exhibited skin anomalies such as desquamations traducing as hyperplasia and hyperkeratosis histologically , indurations and increased vulnerability .

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

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

NO_PRETOX_REL

Conclusion No NOEL could be established in this study .

[ "Conclusion", "No", "NOEL", "could", "be", "established", "in", "this", "study", "." ]

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

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

NO_PRETOX_REL

Animals were dosed for 4 cycles , receiving doses of 0 ( control ) , 0.06 , 0.2 and 0.6 mg / kg per day at a dose volume of 2 mL / kg .

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[ "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", "O" ]

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NO_PRETOX_REL

In Weeks 1 , 12 , 25 , 38 and 51 heparinized whole blood was collected from 5 animals / sex / group for determination of blood drug levels .

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

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PRETOX_REL

- decrease in heart rate was noted in male animals on day 8 .

[ "-", "decrease", "in", "heart", "rate", "was", "noted", "in", "male", "animals", "on", "day", "8", "." ]

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

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

PRETOX_REL

Haemorrhages and infarcts were found in a large number of organs .

[ "Haemorrhages", "and", "infarcts", "were", "found", "in", "a", "large", "number", "of", "organs", "." ]

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

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

NO_PRETOX_REL

All animals survived the 13 - week dosing period .

[ "All", "animals", "survived", "the", "13", "-", "week", "dosing", "period", "." ]

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

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

NO_PRETOX_REL

No sex effect was observed except on the first day when measurable levels appeared later in the females than in males .

[ "No", "sex", "effect", "was", "observed", "except", "on", "the", "first", "day", "when", "measurable", "levels", "appeared", "later", "in", "the", "females", "than", "in", "males", "." ]

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

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

NO_PRETOX_REL

This study was designed to establish a no toxic effect level , to estimate the toxicokinetic profile , and to estimate the potential for reversal of any toxic effects within a 4 - week recovery phase .

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

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NO_PRETOX_REL

When compared to controls the administration of COMPOUND_XXX , daily , for 4 weeks produced the following treatment - related changes .

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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" ]

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NO_PRETOX_REL

One high - dose recovery animal was terminated prior to the end of study in response to a condition suspected to be due to an error in dosing .

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[ "O", "B-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "I-DOSE_QUALIFICATION", "O", "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, 15, 16, 16, 0, 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

However , systemic exposure , as indicated by maximum concentrations and a limited number of samples above the lower limit of quantification ( LLOQ , 0.1 ng / mL ) , increased with the dose and with the time period of treatment .

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

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NO_PRETOX_REL

Blood was collected at various time points for toxicokinetic analysis on days 1 and 15 .

[ "Blood", "was", "collected", "at", "various", "time", "points", "for", "toxicokinetic", "analysis", "on", "days", "1", "and", "15", "." ]

[ "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

Theses dermal findings are deemed related to treatment with the test substance .

[ "Theses", "dermal", "findings", "are", "deemed", "related", "to", "treatment", "with", "the", "test", "substance", "." ]

[ "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

Water consumption showed no treatment - related changes in males at any dose level compared to control .

[ "Water", "consumption", "showed", "no", "treatment", "-", "related", "changes", "in", "males", "at", "any", "dose", "level", "compared", "to", "control", "." ]

[ "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

Three males and one female receiving 1.5 / 1.0 mg / kg / occasion were noted as being thin in appearance from Week 7 of the study onwards .

[ "Three", "males", "and", "one", "female", "receiving", "1.5", "/", "1.0", "mg", "/", "kg", "/", "occasion", "were", "noted", "as", "being", "thin", "in", "appearance", "from", "Week", "7", "of", "the", "study", "onwards", "." ]

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

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

NO_PRETOX_REL

The degree of thickening was dose - dependant up to 1000 mg / kg / day , when a plateau was reached .

[ "The", "degree", "of", "thickening", "was", "dose", "-", "dependant", "up", "to", "1000", "mg", "/", "kg", "/", "day", ",", "when", "a", "plateau", "was", "reached", "." ]

[ "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" ]

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

NO_PRETOX_REL

The lists of individual data are given in Appendix 2 .

[ "The", "lists", "of", "individual", "data", "are", "given", "in", "Appendix", "2", "." ]

[ "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

The purpose of this study was to establish the toxicologic effects of COMPOUND_XXX , a protein - tyrosine kinase inhibitor , when administered to rats for at least 26 weeks .

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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", "O" ]

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

NO_PRETOX_REL

No test article related microscopic findings were noted in the animals that were dosed twice weekly .

[ "No", "test", "article", "related", "microscopic", "findings", "were", "noted", "in", "the", "animals", "that", "were", "dosed", "twice", "weekly", "." ]

[ "O", "O", "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, 3, 4, 4, 0 ]

NO_PRETOX_REL

XXXX ) and Placebo to COMPOUND_XXX ( patches , batch no .

[ "XXXX", ")", "and", "Placebo", "to", "COMPOUND_XXX", "(", "patches", ",", "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

III ) , resp .

[ "III", ")", ",", "resp", "." ]

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

[ 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

The rats received daily doses of 0 ( CMC - vehicle control ) , 0 ( distilled water control ) , 10 , 40 , 180 , and 800 of Ro mg / kg / day 24-7429/002 at a constant volume of 5 ml / kg / day .

[ "The", "rats", "received", "daily", "doses", "of", "0", "(", "CMC", "-", "vehicle", "control", ")", ",", "0", "(", "distilled", "water", "control", ")", ",", "10", ",", "40", ",", "180", ",", "and", "800", "of", "Ro", "mg", "/", "kg", "/", "day", "24-7429/002", "at", "a", "constant", "volume", "of", "5", "ml", "/", "kg", "/", "day", "." ]

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

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PRETOX_REL

Minimal to moderate liver alterations were present in both treated groups with substantial individual variations in occurrence and severity .

[ "Minimal", "to", "moderate", "liver", "alterations", "were", "present", "in", "both", "treated", "groups", "with", "substantial", "individual", "variations", "in", "occurrence", "and", "severity", "." ]

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

[ 1, 14, 14, 8, 9, 0, 0, 0, 12, 13, 13, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

NO_PRETOX_REL

Female animals appeared to be exposed to higher levels of COMPOUND_XXX compared to males .

[ "Female", "animals", "appeared", "to", "be", "exposed", "to", "higher", "levels", "of", "COMPOUND_XXX", "compared", "to", "males", "." ]

[ "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 ]

PRETOX_REL

Total food consumption was slightly low for males at 50 mg / kg / day and for males and females during treatment at 75 mg / kg / day .

[ "Total", "food", "consumption", "was", "slightly", "low", "for", "males", "at", "50", "mg", "/", "kg", "/", "day", "and", "for", "males", "and", "females", "during", "treatment", "at", "75", "mg", "/", "kg", "/", "day", "." ]

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

[ 0, 2, 6, 0, 1, 14, 0, 5, 0, 3, 4, 4, 4, 4, 4, 0, 0, 5, 7, 7, 0, 0, 0, 3, 4, 4, 4, 4, 4, 0 ]

NO_PRETOX_REL

Systemic exposure to COMPOUND_XXX was generally dose proportional .

[ "Systemic", "exposure", "to", "COMPOUND_XXX", "was", "generally", "dose", "proportional", "." ]

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

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

PRETOX_REL

Decedent : On study day 13 , one satellite female at 30 mg / kg / day was sacrificed due to animal welfare reasons and selected for necropsy .

[ "Decedent", ":", "On", "study", "day", "13", ",", "one", "satellite", "female", "at", "30", "mg", "/", "kg", "/", "day", "was", "sacrificed", "due", "to", "animal", "welfare", "reasons", "and", "selected", "for", "necropsy", "." ]

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

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

PRETOX_REL

Analogously , hyperinsulinemia as a consequence of an insulin - secreting tumor has also been associated with development of peripheral nerve pathology [ 6 ] .

[ "Analogously", ",", "hyperinsulinemia", "as", "a", "consequence", "of", "an", "insulin", "-", "secreting", "tumor", "has", "also", "been", "associated", "with", "development", "of", "peripheral", "nerve", "pathology", "[", "6", "]", "." ]

[ "O", "O", "B-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, 0, 8, 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

None of the observed effects apart from the vomiting is regarded as adverse .

[ "None", "of", "the", "observed", "effects", "apart", "from", "the", "vomiting", "is", "regarded", "as", "adverse", "." ]

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

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

NO_PRETOX_REL

individual body weights and food consumption were recorded weekly .

[ "individual", "body", "weights", "and", "food", "consumption", "were", "recorded", "weekly", "." ]

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

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

NO_PRETOX_REL

Food consumption was unchanged during the treatment period in both genders , and in females during the recovery period .

[ "Food", "consumption", "was", "unchanged", "during", "the", "treatment", "period", "in", "both", "genders", ",", "and", "in", "females", "during", "the", "recovery", "period", "." ]

[ "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

XXXXX .

[ "XXXXX", "." ]

[ "O", "O" ]

[ 0, 0 ]

NO_PRETOX_REL

The reversibility from the effects was also assessed during a 2 - week recovery period .

[ "The", "reversibility", "from", "the", "effects", "was", "also", "assessed", "during", "a", "2", "-", "week", "recovery", "period", "." ]

[ "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 ]

PRETOX_REL

Only very slight erythema was noted in animals dosed twice weekly .

[ "Only", "very", "slight", "erythema", "was", "noted", "in", "animals", "dosed", "twice", "weekly", "." ]

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

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

NO_PRETOX_REL

Organ Weights The comparison of mean values of absolute and relative organ weights of the test article treated animals to the corresponding values of the control animals and a statistical analysis by using the DUNNETT test showed a compound - related difference between the test article treated animals and the controls ( see Text Tables in the appendix Several other partly statistically significant differences in group mean absolute and / or relative organ weights were considered incidental and not compound - related as they were slight , not dose - related , observed only in one sex and / or unaccompanied by correlated morphologic findings .

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NO_PRETOX_REL

The No Observed Effect Level in this study was 50 ppm in both sexes , equating approximately to 3.5 mg / kg / day in males and 4.1 mg / kg / day in females .

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PRETOX_REL

At necropsy all group III ( 30/60 mg / kg ) - males showed a reddish discoloration of the mesenteric lymph nodes .

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NO_PRETOX_REL

It is deemed related to treatment with the test substance .

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NO_PRETOX_REL

The details can be taken from the pathology report in the appendix of the report .

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PRETOX_REL

In females , mean absolute liver weight , liver to body weight and liver to brain weight ratios were increased by 20 % , 24 % and 18 % , respectively .

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NO_PRETOX_REL

There were no consistent differences in exposure to COMPOUND_XXX or YYYYY between males and females .

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NO_PRETOX_REL

All organ weight changes were reversible following the recovery period .

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

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PRETOX_REL

Laboratory diagnostics : - decrease in index of erythropoiesis / granulopoiesis , decrease in the number of erythropoietic cells and an increase in the number of neutrophilic cells was observed in the bone marrow examination in male animals ( interim sacrifice on day 10 ) .

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PRETOX_REL

In all high - dose rats , the ear pinnae , xiphoid cartilages , and skin were discolored yellow .

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PRETOX_REL

In conclusion , oral administration of COMPOUND_XXX by gavage to rats for 4 weeks resulted in test article - related statistically significant decreases in mean body weight and mean body weight gain in males at 60 mg / kg / day , organ weight changes in both sexes at 60 mg / kg / day and renal changes in males at doses ≥ 6 mg / kg / day .

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PRETOX_REL

Otherwise only background findings common to Füllinsdorfer Albino - rats were seen .

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NO_PRETOX_REL

The relevance of these findings remains unclear .

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PRETOX_REL

Microscopic examination of the joints revealed growth plate thickening , indicating pharmacological activity , without any adverse changes .

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NO_PRETOX_REL

( ~ ~ Microscopic investigation of the urinary sediments involving differentiation into bacteria , epithelial cells , leucocytes , erythrocytes and amorphous salts did not bring to light any notable quantitative or qualitative differences between the control groups and the treatment groups up to and including group Ill as regards the composition of the sediments .

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NO_PRETOX_REL

There were no COMPOUND_XXX - related changes at 40 mg / kg / day .

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NO_PRETOX_REL

The following investigations were performed : mortality , clinical signs , body weight , urinalysis , toxicokinetic investigations , necropsy , macroscopic and microscopic examinations ( including immunohistochemistry ) , and pharmacogenomic investigations .

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NO_PRETOX_REL

The study was designed to establish a no - observed - adverse - effect level ( NOAEL ) , to estimate the toxicokinetic profile , and to estimate the potential for reversal of any toxic effects within a 4 - week postdosing phase .

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PRETOX_REL

COMPOUND_XXX - related reductions in neutrophil , lymphocyte , monocyte and eosinophil counts at 30 and 75 mg / kg were associated with myeloid series changes ( maturation arrest ) observed during bone marrow cytological evaluation .

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NO_PRETOX_REL

No treatment - related effects on hematological parameters , organ weights , macroscopic or microscopic findings were observed at either 100 or 300 mg / kg / day .

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PRETOX_REL

Adrenal cortical hypertrophy noted at the high dose as well as reductions in thymus and spleen weights were attributed to a stress - like response to hypoglycemia .

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NO_PRETOX_REL

a. Clinical observations The table for the evaluation of the nutritional state can be found in the appendix of the report .

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NO_PRETOX_REL

Blood samples for hematology and clinical chemistry were collected at pretest , and on day 14 .

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PRETOX_REL

In histopathology treatment related findings were observed in the hemolymphatic system , gastrointestinal tract , female reproductive tract , kidney , bone , salivary glands , lung , trachea and thyroid gland .

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PRETOX_REL

8 ) Increased weight of the salivary glands was noted in females in the 50 mg / kg group .

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NO_PRETOX_REL

The reversibility of treatment - related effects was assessed following a four - week recovery period .

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NO_PRETOX_REL

Toxicokinetic analysis revealed a dose - dependent systemic exposure .

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

NO_PRETOX_REL

All findings showed a tendency to normalization by the end of the recovery period .

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PRETOX_REL

The number of neutrophilic granulocytes was slightly increased ( statistically significant ) , whereas the absolute basophil number was slightly decreased ( statistically significant ) .

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