javicorvi/pretoxtm-dataset huggingface dataset:
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 .
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 .
The principal test article - related microscopic findings consisted of thyroid changes ( ~ 0.06 mg / kg / day ) , depletion of lymphoid tissue ( ~ 0.2 mg / kg / day ) , thymic atrophy ( 0.6 mg / kg / day ) , decreased bone marrow hematopoiesis ( 0.6 mg / kg / day ) , and intracellular pigment deposition at various sites ( ~ 0.2 mg / kg / day ) .
Changes unrelated to COMPOUND_XXX : None Body Weights ( Tables 2 - 1 to 2 - 3 , Appendices 2 - 1 to 2 - 12 ) Changes related to COMPOUND_XXX : At 50 mg / kg , significant decreases were noted on Day 29 , and increases were noted on Days 64 to 78 , and 113 to 134 compared to the controls .
From macroscopic and microscopic observations at premature and / or terminal kill , degenerative / atrophic changes were seen in the haemolymphopoietic system , lungs , intestines and ovaries mainly at the dose level of 40 mg / kg and were considered as toxicological targets of the compound COMPOUND_XXX as follows : - the bone marrow hypocellularity was noted in all animals given 40 mg / kg and was the histological correlate of the fluid femoral bone marrow seen for 5/10 males and 4/7 prematurely killed females given 40 mg / kg .
High - dose group 70 mg / kg / day : week 4 to the end of the treatment period - Leukopenia and mild myeloid hypoplasia of bone marrow - Minimally to slightly decreased platelet counts - Testes : decreased weight , severe tubular atrophy , moderate vacuolation of the seminiferous epithelium , slight interstitial cell hyperplasia , absence of spermatozoa in the epididymides - Moderate to marked cortical atrophy of the thymus in 2/6 dogs Mid-dose group ( 2 mg / kg / day ) - Body weight loss in 2/5 females - Mild myeloid hypoplasia of bone marrow - Testes : decreased weight , marked tubular atrophy , moderate vacuolation of the seminiferous epithelium , slight interstitial cell hyperplasia , absence of spermatozoa in the epididymides - Slight cortical atrophy of the thymus in 2/5 dogs Low - dose group ( 0.2 mg / kg / day ) In l / 3 males : - Testes : slight tubular atrophy , moderate vacuolation of the seminiferous epithelium , moderate germ cell degeneration , oligospermia in the epididymides .
Other microscopic findings comprised epithelial vacuolation / hypertrophy , pigment deposition , necrosis , fibrin thrombi and vasculitis / perivasculitis in the gall bladder ; glandular dilatation , inflammatory cell infiltration with vasculitis / perivasculitis , mucosal atrophy and erosion in the small and large intestine and epithelial necrosis / vacuolation in the epididymides and prostate .
The higher exposure in females resulted in compound - related effects seen either exclusively or at lower doses in females , including partly to completely reversible clinical chemistry changes in males at 110 mg / kg / day and females at ≥ 30 mg / kg / day ; irreversible increases in adrenal gland and kidney weight and partially reversible liver weight increases in females at 110 mg / kg / day ; reversible macroscopic light pale colored kidneys in females at ≥ 30 mg / kg / day ; and partially to completely reversible microscopic kidney findings in males at 110 mg / kg / day and females at ≥ 10 mg / kg / day , as well as reversible and nonadverse microscopic liver findings in females at 110 mg / kg / day .
At 50 mg / kg / day , microscopic findings consisted of hemorrhagic and / or cystic corpora lutea lutea and hemosiderin - laden macrophages in ovaries , foamy macrophage accumulation in lungs , focal angiectasis of the adrenal cortex , hypertrophy of the masseter muscle , focal mineralization and hyperplasia of renal pelvic epithelium , and focal new bone formation .
Since no histological heart lesions related to treatment with COMPOUND_XXX were observed at 80 mg / kg after 4 weeks treatment or 60 mg / kg after 4 or 26 weeks treatment in previous toxicity studies in rats ( Studies 0510076 , 0370146 and 0580158 ) at similar systemic exposure to COMPOUND_XXX , the increase of these foci in some treated animals appears to be more likely an exacerbation of a background lesion due to treatment or an incidental finding not related to treatment rather than a direct effect of COMPOUND_XXX .
In conclusion , oral administration of the thyroid toxicant propylthiouracil ( PTU ) to male rats for 5 , 12 or 26 days produced time dependent changes in thyroid hormones ( increases in TSH , decreases in T3 and T4 ) and organ weight increases with correlative microscopic changes in the thyroid ( follicular cell hypertrophy ) and pituitary ( pars distalis hypertrophy ) which were consistent with a sustained disruption of the hypothalamic - pituitary - thyroid axis .
XXXXX ) was administered once weekly by intravenous injection as a solution in vehicle ( 20 % proypylene glycol / 80 % 0.1 M lactic acid and 4.3 % mannitol ) to 3 groups ( 3 sex / group ) of male and female beagle dogs ( Canis familiaris ) at doses of 0.2 , 0.6 and 1.2 mg / kg / week for 13 weeks .
Discussion Administration of COMPOUND_XXX 1 for 4 weeks in Wistar rats induced the premature kill of 7/15 females given 40 mg / kg due to poor clinical conditions , severe decrease in circulating leukocytes , lymphocytes and neutrophils owing to a decrease in myelocytic series noted in the bone marrow leading to a low myeloid to erythroid ratio , decreases in serum protein and albumin concentrations , and partially electrolyte disorders .
Compound - related organ weight ( absolute and covariant ) decreases were present at doses ≥ 10 mg / kg and included decreases in submaxillary salivary gland weights ( doses ≥ 10 mg / kg in males ; doses ≥ 30 mg / kg in females ) , adrenal ( doses ≥ 30 mg / kg in males and females ) , liver weights ( doses ≥ 30 mg / kg in males and 75 mg / kg in females ) and prostate weights ( males at ≥ 10 mg / kg ) .
Treatment - related clinical signs consisted of fecal changes ( females at doses ≥ 0.2 mg / kg ; males at 1.2 mg / kg ) and limited hindlimb usage / abnormal gait ( individual males at 0.2 and 1.2 mg / kg ; 3/5 females at 1.2 mg / kg ) with affected limbs often red , slightly swollen and warm to touch .
At the end of the dosing period , at 1.0 mg / kg , the mean AUC ( 0 - 24h ) was 76.7 ± 18.5 ng.h / mL and 88.4 ± 37.8 ng.h / mL for males and females respectively , Cmax , was 23.2 ± 6.63 ng / mL and 22.9 ± 8.44 ng / mL for males and females respectively and tmax , was 0.5 ± 0 h and 0.6 ± 0.3 h for males and females respectively .
The following rounded values of Cmax and AUC ( o - 24h ) were observed on day 14 : COMPOUND_XXX Male Female COMPOUND_XXX - 666 Male Female 11 121 120 14 10 53 14 103 102 17 16 60 185 1810 1113 199 168 735 247 1637 1003 242 239 942 Cmax ( ng / ml ) 36 mg / day 108 mg / day 216 mg / day AUC o - 24h ( h.ng / ml ) 36 mg / day 108 mg / day 216 mg / day Because of the great between - animal variability , an increase of the concentration with the dose could not be demonstrated .
C0040 ) , was suspended in aqueous 0.5 % hydroxylpropyl methylcellulose ( Methocel ) solution and orally administered by gavage once daily to male Wistar rats over 3 days ( 8 animals per group ) or 4 weeks ( 10 animals plus 3 additional animals for toxicokinetics per group ) at 40 or 80 mg / kg using a dosage volume of 5 mL / kg .
Clinical Signs ( Tables 1 - 1 to 1 - 30 , Appendices 1 - 1 to 1 - 90 ) Changes related to COMPOUND_XXX : At 10 mg / kg and higher , discoloration ( whitish bands or whiteness ) of incisors was observed in all animals except for 2 moribund or early sacrificed animals ( Animal Nos. 03F04 and 03F10 ) from Day 21 as earliest through to the end of dosing period .
The tables give the counts of ASAT , ALAT , APh , GLDH , GGT , LDH , CK , GLUCOSE , CHOL , TRIGL , CREA , UREA , BILF - t , PROT , ALBUMIN , Na , K , Ca , Cl , P , Fe , Mg , T3 , 14 , TBC , 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 In all the other clinicochemical parameters determined no changes were detected up to and including group III .
In conclusion , once - weekly dermal administration of COMPOUND_XXX Nail Lacquer containing different concentrations of hydrogen malate ( 100 , 200 or 270 mg base / g formulation ) at 1 mL / kg resulting in dosages of 100 , 200 or 270 mg base / kg or of the Placebo Nail Lacquer to Göttingen minipigs over about 13 weeks was generally well tolerated without clear indication of systemic toxicity .
Laboratory diagnostics All relevant compound - related or suspected compound - related effects observed in female animals can briefly be summarized as follows : Findings from the low dose of 5 mg / kg COMPOUND_XXX upwards : e increase in alkaline phosphatase on day 28 , which lasted until day 49 in animals of the high dose ( group 6 ) of 50 mg / kg COMPOUND_XXX In addition , findings from the mid dose of 15 mg / kg COMPOUND_XXX upwards : e increase in urinary volume associated with a decrease in specific gravity and an increase in PH value on day 22 , which was absent on day 51 Additional findings at the high dose of 50 mg / kg COMPOUND_XXX e increase in alanine aminotransferase on day 28 , which was absent on day 49 e decrease in calcium on day 28 , which lasted until day 49 e slight increase in gamma globulin on day 28 , which lasted until day 49 .
Therefore , the NOEL is considered to be below 0.05 mg / kg / day and the NOAEL is set at 0.05 mg / kg / day with a C max / AUC 0 - 24 levels on Day 29 of 1.04 / 0.90 and 1.62 / 2.30 [ ng / mL / ng.h / mL ] in males and females , respectively .
Eighty ( 80 ) Wistar rats were allocated to 8 groups ( 5 animals / sex / group ) and treated by the dermal route either once daily from Days 1 - 28 or twice weekly from Days 1 - 28 with the control article or the test articles , COMPOUND_XXX 100 mg / g Nail Lacquer ; COMPOUND_XXX 200 mg / g Nail Lacquer ; or COMPOUND_XXX 270 mg / g Nail Lacquer , at dose levels of 100 , 200 , or 270 mg / kg / day .
Summary of results and discussion Following suspected or clear - cut compound - related findings were observed : From 35 mg / kg COMPOUND_XXX onwards : - single or repeated vomitus over several days with dose - dependently increasing frequency and incidence in two animals of group 2 and all animals of groups 3 and 4 - _ slight decrease in systolic blood pressure in individual animals of all groups From 100 mg / kg COMPOUND_XXX onwards : - sialorrhea with dose - dependently increasing frequency and incidence in one animal of group 3 and all animals of group 4 - decrease in food intake in one animal of group 3 ( no. 8566 ) and in all animals of group 4 - decrease in water consumption in one animal of group 3 ( no. 8566 ) and in all animals of group 4 - distinct loss of body weight in one animal of group 3 ( no 8566 ) and in all animals of group 4 - decrease in heart rate in one animal of group 3 ( no. 8566 ) and in all animals of group 4 ; this effect provoked a prolongation of the PQ - and QT - intervals in the above - mentioned animals - _ slight increase in alkaline phosphatase on day 27 - slight increase in fibrinogen on day 27 - slight increase in sedimentation rate in one animal only of group 3 - emaciation of one animal each in group 3 and 4 - hypocellularity of bone marrow of femur and sternum .
Following once weekly dosing with COMPOUND_XXX for 13 weeks at 1.2 mg / kg , the AUC for COMPOUND_XXX was 220 ng · hr / mL for males and 193 ng hr / mL for females and the Cmax was 185 ng / mL for males and 169 ng / mL for females ; for metabolite BJB432 the AUC was 20.5 ng · hr / mL for males and 15.5 ng · hr / mL for females and the Cmax was 5.70 ng / mL for males and 6.65 ng / mL for females .
Summary of results At the low dose of 5 mg / kg COMPOUND_XXX per day and higher : Clinical examinations : - vomiting occurred in male and female animals ( reversible after termination of treatment ) - a clear increase of the heart rate was noted in one male in week 3 ( 0.5 hours after administration ) and in two female animals in week 3 ( 0.5 hours after first administration ) and in week 4 ( prior to next administration ) .
Conclusions As the findings observed after the low and mid dose are either of minor biological relevance ( sialorrhea and decrease in locomotive activity , vomitus , slight and reversible decreases in parameters of red blood cells ) or explainable by the pharmacological action ( reversible morphological alterations at reproductive organs ) of the compound which interferes with the endocrine system of the dog , the dose of 15 mg / kg COMPOUND_XXX is regarded as NOAEL in respect of the future use in female breast cancer patients .
At the end of the dosing period , at 1.0 mg / kg , the mean AUC ( 0 - 24h ) was 71.2 ± 37.3 ng.h / mL and 91.8 ± 37.6 ng.h / mL for males and females respectively , Cmax , was 16.0 ± 9.20 ng / mL and 24.2 ± 13.7 ng / mL for males and females respectively and tmax , was 0.750 ± 0.289 h and 0.625 ± 0.250 h for males and females respectively .
Compound - related microscopic findings were noted from 30 mg / kg / day in the diaphragm in males ( myofiber necrosis and regeneration ) and at 100 mg / kg / day in the adrenal gland in females ( increase in severity of the cell vacuolation in the zona glomerulosa ) , in the mesenteric lymph node in both sexes ( increase in enlarged pigmented macrophages aggregates number ) , in the kidney in both sexes ( tubular cell degeneration and regeneration , tubular cell anisokaryosis and karyomegaly , tubular dilatation and tubular cell mitoses ) affecting most tubules ( loop of Henle tubules and collecting ducts ) in the inner stripe of the outer medulla in males and females with a higher severity in males , and scattered tubules ( loop of Henle tubules , distal tubules and collecting ducts ) in the outer stripe of the outer medulla and in the cortex in males .
Targets for toxicity : - Haemolymphopoietic system : decrease in platelet , erythrocyte and leukocyte counts and atrophic changes in the thymus - Changes observed in the spleen ( extramedullary haemopoiesis in the red splenic pulp ) and bone marrow ( increased number of megakaryocytes ) were considered as a rebound effect secondary to the decreased blood cell parameters and changes in the Mesenteric Lymph Nodes ( sinusal haemorrhage and large cells with large nucleus ) are also probably secondary to the decreased blood cell parameters .
upwards : - decrease in packed cell volume ( p < 0.05 - p < 0.01 ) in males and females on day 25 , reversible at the mid dose on day 53 - decrease in mean cell volume ( p < 0.01 ) in males and females on day 25 , reversible at the mid dose on day 53 - increase in mean cell hemoglobin concentration ( p < 0.01 ) in males and females on day 25 , reversible at the mid dose on day 53 - increase in platelet count ( p < 0.01 ) in males and females at the mid dose on day 25 , reversible on day 53 Findings observed in animals exposed to COMPOUND_XXX at a daily dose of 160 pmol / kg bw .
- minimal to slight glomerulopathy beginning at group II - minimally to slightly increased.PAS positive reaction of tubules and / or glomerula beginning at group It The lymphoreticular / hematopoetic system showed : - minimal to moderate atrophy of thymus and minimal to slight atrophy of spleen beginning at group Il - slightly to markedly increased hematopoiesis in the spleen beginning at group | - increased iron positive pigment deposition in the spleen beginning at group | - minimally to slightly increased perifollicular granulocytic infiltration in the spleen oa beginning at group I !
In the course of the study the following compound - related or suspected compound - related findings were observed : At the mid dose group of 0.17 mg / kg COMPOUND_XXX and higher : - diarrhea in male animals - decrease in eosinophil count in males on day 6 after the first administration , decrease in albumin and albumin / globulin quotient in females on day 6 after the third administration and prolongation in activated partial thromboplastin time in males on day 6 after the sixth administration - single cell necrosis in the liver .
Key treatment - related findings included : • Slight , transient increase in food consumption at 150 and 400 mg / kg / day ; • Dose - proportional reductions in plasma glucose at all doses ; • Reversible decreases in serum glucose in males and females at 400 mg / kg / day ; • Reversible decreases in thymus and spleen weights at 400 mg / kg / day ; • Reversible increases in adrenal gland weight which correlated with cortical hypertrophy at 400 mg / kg / day ; • Sciatic nerve fiber degeneration at 150 and 400 mg / kg / day that showed resolution after four weeks of recovery .
TT 2 : 2 Determination of organ weights , fixation and processing of tissues for histological examination - liver ( W ) * - mandibular lymph nodes - kidneys ( W ) - bone [ femur , sternum , both with - urinary bladder bone marrow ] - heart ( W ) - brain [ cerebrum , cerebellum , - atrium medulla oblongata ] ( W ) - lungs ( W ) * - spinal cord [ cervical segment ] - aorta thoracalis - peripheral nerve [ N. saphenus ] - vein [ vena cava caudalis ] - eye - trachea - harderian glands - esophagus - tongue - pituitary gland ( W ) [ B ] - salivary glands [ submandibular ] ( W ) - thyroid with parathyroid glands ( W ) - stomach - adrenal glands ( W ) - small intestine [ duodenum , - ovar ( W ) * jejunum , ileum ] - uterus [ horn , corpus , cervix ] ( W ) * - large intestine [ cecum , colon , rectum ] - vagina - pancreas ( W ) - mammary gland - skeletal muscle [ M. gastrocnemius ] - skin - and any other organ / tissue with - thymus ( W ) * macroscopic alterations , if necessary - spleen ( W ) for evaluating a diagnosis - iliac lymph nodes ( W ) ( w ) = Organ weight was recorded [ B ] = BOUIN 's fixative bold print = examined histologically in controls and top dose group * = additional histological examination in low and intermediate dose groups Bone marrow No compound - related effect was observed .
Sprague - Dawley derived rats ( 25 animals / sex / group ) were administered the hydrogen tartrate salt of COMPOUND_XXX at doses ofO , 0.2 , 0.6 , 1.8 or 3.0 mg / kg / day ( base equivalent dose levels 0 , 0.1 , 0.4 , 1.1 and 1.8 mg / kg / day , respectively ) by gavage in 1 % CMC for fifty - two weeks .
COMPOUND_XXX ( Batch no. 0351002 ) was administered orally by gavage as a suspension in 0.5 % ( w / v ) hydroxypropylmethylcellulose ( 0.5 % HPMC ) Type E4M Premium , aqueous solution , to four groups of beagle dogs ( N = 3 / sex / group ) at doses of 0 , 5 , 15 and 45 mg / kg / day base ( equivalent to 0 , 5.3 , 16.0 and 48.1 mg / kg COMPOUND_XXX salt , respectively based on the salt / base ratio of 1.069 ) .
Following once weekly dosing with COMPOUND_XXX for 13 weeks at 3.0 mg / kg , the AUC for COMPOUND_XXX was 1000 ng · hr / mL for males and 660 ng hr / mL for females and the Cmax was 746 ng / mL for males and 493 ng / mL for females ; for metabolite YYYYY the AUC was 298 ng · hr / mL for males and 178 ng · hr / mL for females and the Cmax was 79.2 mg / mL for males and 40.7 ng / mL for females .
In addition , at the high dose group of 0.5 mg / kg COMPOUND_XXX : - diarrhea in female animals - decrease in food consumption in female animals usually occurring 5 - 8 days after administration - increase in total alpha globulin in females mainly on day 6 after administration , decreases in reticulocytes in males and females mainly on day 6 after administration , decreases in MCHC in females from day 3 to day 17 after the sixth administration , decreases in WBC , lymphocyte count , eosinophil count in males and females between days 3 and 10 after administration , decrease in basophil count in males on days 3 and 6 after the sixth administration , slight increase in platelet count in females between days 6 and 13 after administration - in the bone marrow approximately 3 weeks after the sixth administration : decrease in mature erythrocytes in males and increase in the ratio of immature to mature granulocytes in females as well as decrease in the ratio of erythopoiesis to granulopoiesis in males - liver findings : yellowish discoloration and focal gray - white discoloration / s ; periportal hepatocellular hypertrophy ; periportal vacuolation , in one male associated with an acute focal necrosis ; focal fatty changes .
SUMMARY COMPOUND_XXX , a fungicide of the SDH - carboxamide family ( batch number 111111 : a white solid , 99.7 % w / w purity ) was administered continuously via the diet to groups of Wistar rats ( 5 / sex / group ) for at least 28 days at concentrations of 50 , 350 and 2 000 ppm ( equating approximately to 3.5 , 25 and 137 mg / kg / day in males and 4.1 , 28 and 138 mg / kg / day in females ) .
The changes included atrophy of the bone mmTow , lymphoid atrophy , lymphocytolysis and vacuolation in lymphatic organs / tissues , histiocytosis in lymphatic tissues , hemorrhage in the mesenteric lymph node , accumulation of alveolar macrophages in the lung , tubular necrosis and basophilia in the kidneys , hemon · hage and hemorrhagic corpora lutea in the ovaries , atrophy of uterus , prostate and seminal vesicles , disturbance of the estrus cycle , follicular atrophy in the thyroid gland and vacuolation and single cell necrosis in the mucosa of the small intestine and uterus , tracheal epithelium , bile duct epithelium in the liver , Harderian glands , salivary glands and thyroid follicular epithelium .
Degenerative / necrotic hepatocellular changes were visualized only at 320 mg / kg and only for a few rats ( single hepatocellular necrosis for males , vacuolar degeneration / necrosis for females ) , whereas the regenerative changes ( hepatocellular anysokaryosis / karyomegalies and / or mitoses ) were already seen for some females at 160 mg / kg , and were seen for more males and females at 320 mg / kg .
Ophthalmoscopic examinations not reveal any ocular changes attributable to treatment with COMPOUND_XXX and there were no electrocardiographic abnormalities associated with the intravenous administration ofCOMPOUND_XXX Test article - related organ weight decreases were noted in the thyroid in both sexes ( ~ 0.06 mg / kg / day in females , 0.6 mg / kg / day in males ) and in the liver of males only ( ~ 0.2 mg / kg / day ) .
In conclusion , COMPOUND_XXX administered 3 times per week to male and female rats for at least 4 weeks at doses of 3 , 10 and 30 mg / kg resulted in reversible decreases in body weight gain in females at 30 mg / kg , reversible decreases in target organ weights at doses ≥ 3 mg / kg , and reversible histopathology at doses ≥ 10 mg / kg .