javicorvi/pretoxtm-dataset huggingface dataset:
Key treatment - related findings included : Moribund sacrifice of one 450 mg / kg / day female on day 2 due to severe hypoglycemia ; In - life observations of splayed posture , hypoactivity , piloerection , and increased respiration rate in surviving females in the 450 mg / kg / day dose group ; Slightly increased food consumption in the 450 mg / kg / day dose group ; Dose - proportional reductions in plasma glucose at all doses ; An increase in adrenal weights at 450 mg / kg / day ; An approximate 30 - 50 % decrease in serum glucose in males and females at 450 mg / kg / day and in females at 150 mg / kg / day ; Sciatic nerve fiber degeneration at 150 and 450 mg / kg / day .
On days 22 - 23 the AUC ( 0 - 24h ) values were 14.2 , 35.2 , and 151 ( ng.h / mL ) and 8.97 , 42.8 in males , and 123 ( ng.h / mL ) in females at 0.15 , 0.5 and 1.5 mg / kg / day , respectively .
On days 1 - 2 the AUC ( 0 - 24h ) values were 23.5 , 63.8 , and 220 and ng.h / mL in males and 9.89 , 74.9 , and 239 ( ng.h / mL ) in females at 0.15 , 0.5 and 1.5 mg / kg / day , respectively .
e wet - matted fur at several locations ( throat , thorax , fore limbs and nose in males and females ) followed by thinning of fur or hairless areas at these locations were noted also in males and females Â ¢ insertion of gavage was difficult mainly in female animals e disturbances in gait , curved back , drawn in flanks , eyelid closure were noted only in female animals Increased sialorrhea was observed in all animals of all groups ( treatment and control group ) but with higher incidence in the treatment groups ( with dose - dependent increase ) .
These consisted of decreased thymus weights at doses ≥ 1 mg / kg ( males ) and 3 mg / kg ( females ) , lymphoid atrophy in both spleen and thymus at doses ≥ 1 mg / kg ( both sexes ) , and , in the spleen , increased pigment deposit at 3 mg / kg ( both sexes ) and increased extramedullary hematopoiesis at 3 mg / kg ( males ) .
Treatment with the positive control agent propylthiouracil , a model thyroid toxicant , resulted in time - dependent , moderate to severe and statistically significant changes in thyroid hormone levels ( increases in TSH , decreases in T3 , T4 and free T4 ) , organ weight increases in pituitary and thyroid which correlated with the macroscopic change of enlarged thyroid and microscopic changes in the thyroid ( follicular cell hypertrophy ) and pituitary ( pars distalis hypertrophy ) .
XXXXX ) was administered once weekly by intravenous injection as a solution in vehicle ( 20 % propylene glycol / 80 % 0.1 M lactic acid and 4.3 % mannitol ) to 3 groups ( 10 - 12 / sex / group ) of male and female Han Wistar rats at doses of 0.3 , 1.0 and 3.0 mg / kg for at least 13 weeks .
Test article - related microscopic observations were present in spleen ( decreased extramedullary hematopoiesis ) in females only at 30 mg / kg , thymus ( decreased cortical lymphocyte population ) in females only at 30 mg / kg , and thyroid ( decreased colloid and an increased cytoplasmic vacuolation of the follicular epithelial cells ) in females at 30 mg / kg and males at doses ≥ 10 mg / kg .
At 100 mg / kg / day , samples from the kidney outer medulla were examined in electron miroscopy and compound - related ultrastructural changes were noted in the descending thin limb of the loop of Henle ( cell regeneration ) in the inner stripe of the outer medulla , the thick ascending limb of the loop of Henle ( cell degeneration / necrosis , increase in lysosomes number containing laminated membrane structures ) in the outer medulla ( both inner and outer stripes ) , in the outer medullary collecting ducts ( cell degeneration / necrosis ) , myelin figures ) and in the inner medullary collecting ducts ( myelin figures ) .
The reference item ( as hydrochloride salt ) , batch No. 3 ( Labjournal ID : E-11502-058 ) , was dissolved in 80 mM sodium citrate buffer and administered to two groups each of 20 male rats at dosages of 5 and 15 mg base / kg / day and a dosage volume of 5 mL / kg , once daily , 7 days a week , for 2 or 4 weeks .
Compound - related microscopic changes were present at doses ≥ 10 mg / kg and included bone marrow atrophy ( females at doses ≥ 10 mg / kg , males at ≥ 30 mg / kg ) , increased pigment in the spleen ( both sexes at doses ≥ 10 mg / kg ) , thyroid follicular hypertrophy ( doses ≥ 10 mg / kg ) , thymic atrophy ( doses ≥ 30 mg / kg ) , increases in the frequency of oestrus phase of cycle ( 75 mg / kg ) , erythrophagocytosis of the mesenteric lymph node ( 75 mg / kg ) , lymphoid atrophy ( doses ≥ 30 mg / kg ) , atrophy of the male mammary gland ( doses ≥ 30 mg / kg ) .
At the end of the 26 - week dosing period , mean body weight was reduced in males by 4.7 , 11 and 15 % at doses of 10 , 30 and 75 mg / kg respectively , relative to concurrent controls ; mean body weight gain was reduced in males by 10 , 19 and 29 % at doses of 10 , 30 and 75 mg / kg and in females by 13 % at 75 mg / kg , relative to concurrent controls .
Additional alterations at 180 mg / kg included infiltration with macrophages in various tissues ( subcutaneous tissue , adipose tissue around preputial glands and prostate ) , subcutaneous edema , accumulation of histiocytes in subcutaneous lymph nodes , accumulation of alveolar macrophages in the lung ( frequently accompanied by purulent inflammation ) , bile duct and oval cell hyperplasia with peribiliary fibrosis and macrophage infiltration , vacuolation of bile duct epithelial and sinusoidal lining ( Kupffer ) cells and intravascular accumulation of macrophages in the liver .
- minimal to moderate necrosis of lymphoid follicles in the tonsils beginning at group I - minimal to slight atrophy of lymphoid follicles of the ileum beginning at group II - minimally to slightly increased number of granulocytes in the sternum beginning at group II and in the bone marrow cylinders beginning at group | The teeth showed : - minimal to slight altered dentin composition beginning at group II The large intestine showed : - minimally to slightly increased number of goblet cells beginning at group II The skin showed : - dose - dependant moderate to marked alopecia / degeneration of hair follicles beginning at group I .
Compound related macroscopic findings observed in male and female rats sacrificed at the end of the 4 - week treatment period ( K0 ) and the subsequent 4 - week treatment free recovery period ( R1 ) are summarized in Table 4 Organ 10 10 6 6 10 10 6 6 10 10 6 6 10 10 6 6 In other organs , differences in group mean absolute and / or relative weights between control and treated groups achieved no statistically significance and were regarded as not compound - related as they were minimal and unaccompanied by correlated morphological findings .
Test article - related microscopic changes in the spleen were decreased cellularity , lymphocytic , in all males and 9/10 females at 0.9 mglkg with decreased cellularity , red pulp in 2110 males and increased extramedullary hematopoiesis in all females at 0.9 mg / kg and 9/10 females at both 0.05 and 0.3 mglkg .
At the terminal necropsy , organ weight changes included increased heart weights in males at doses : ; : : : 15 mg / kg / day and in females at 50 mg / kg / day ; decreased spleen weights in males at doses : ; : : : 15 mg!kg / day ; and at 50 mg / kg / day , increased adrenal weights in both sexes ; increased liver and thyroid weights in males ; increased ovary weights and decreased pituitary weights in females and decreased testis weights .
CONCLUSION In conclusion , the administration of COMPOUND_XXX by daily oral gavage for 3 or 10 days at dose levels of 0 , 50 mg / kg / day and 200 mg / kg / day resulted in clinical signs of dehydration and fur staining red , adverse reductions in body weight gain with associated reduced food consumption , minor hematology ( prolonged PT ) , biochemical ( increased BUN ) , significant urinalysis changes ( increased urinary protein and occult blood , glycosuria and polyuria ) , with associated macroscopic ( pale discolouration in medulla or corticomedullary junction ) and microscopic changes ( tubular degeneration / regeneration in the outer medulla ) in the kidney of rats treated with 200 mg / kg / day COMPOUND_XXX .
Summary of results The following compound - related or suspected compound - related findings were noted : At the low dose of 30 mg / kg COMPOUND_XXX and higher ( without dose - dependence if not otherwise mentioned ) : - increased sialorrhea , stained and encrusted mouth / snout - lower water consumption in males - slight decrease in total protein in males on day 24 - slight decrease in relative albumin in females on day 24 - slight decrease in albumin in females on days 24 and 54 ( not decreased at mid dose on day 54 ) - slight dose - dependent increase in total beta globulins in females on day 24 - slight decrease in albumin - globulin quotient in females on days 24 and 54 ( not decreased at mid dose on day 54 ) - dose - dependent decrease of N - demethylase activity in the liver in males - decrease of 7 - ethoxyresorufin deethylase activity in the liver in males in the liver of females In addition , at the mid dose of 100 mg / kg COMPOUND_XXX and higher ( without dose - dependence if not otherwise mentioned ) : - compulsive behavior ( increased frequency of cleaning behavior ) - slight decreases in reticulocyte count in males on day 25 - â € " slight decrease in total protein in females on day 24 - â € " slight dose - dependent decrease in absolute and relative weight of prostate and seminal vesicles ( without histopathological correlate ) - decrease of O - demethylase activity in the liver in males - decrease of aldrin epoxilase activity in the liver in males Additionally , at the high dose of 300 mg / kg COMPOUND_XXX : - slight decreases in red blood cell count and hemoglobin in males on day 25 - slight decrease in albumin in males on day 24 - slight increase in creatinine in males and females on day 24 - decrease of glutathione transferase activity in the liver of females Toxicokinetic evaluation revealed that exposure of female rats was about twice as much as of male rats with regard to Cmax and AUC ( 0 - 24 ) .
COMPOUND_XXX ( batch no. : XXXXX ) was administered orally by gavage as a solution in Purified Water , USP to four groups of male and female Cynomolgus monkeys ( 1 or 2 / sex ) at 0 , 10 , 37.5 and 75 ~ 50 ing / kg b.i.d. ( daily doses of 0 , 20 , 75 and 150 ~ 100 mg / kg / day ) approximately 6 hours apart for at least 2 weeks .
Administration of COMPOUND_XXX was associated with reductions in white blood cell parameters including decreases in white blood cell and lymphocyte counts at doses ≥ 0.3 mg / kg in males and ≥ 1.0 mg / kg in females ; decreases in neutrophil , eosinophil and basophil counts at 3.0 mg / kg , and reductions in red cell parameters ( red blood cell counts , hemoglobin , hematocrit ) and platelet counts , and increases in reticulocyte counts and red cell distribution at doses at doses ≥ 1.0 mg / kg .
Compound - related changes in thyroid hormones measured at the end of the dosing period consisted of slight reductions in thyroid stimulating hormone ( decreased by 13.2 and 14.6 % for females at 1.0 and 3.0 mg / kg respectively ) , slight increases in tetraiodothyronine ( T4 ) ( increased by 21.9 and 18.3 % for females at 1.0 and 3.0 mg / kg respectively ) , and slight increases in T3 levels ( increased by 26 and 19 % respectively for males at 1.0 and 3.0 mg / kg , respectively ) , relative to concurrent controls .
Dose levels of 60 and 180 mg / kg / day were selected based on data from a previous 2 year carcinogenicity study in rats , however , at 180 mg / kg / day , adverse clinical signs of subdued behavior , hunched posture , piloerection and red secretions around the eyes , the nose and the perineal were observed in some animals towards the end of the fourth week of dosing and in a couple of animals as early as the end of the second week of dosing .
At 60 and 600 mg / kg / day , mean jejunal mucosa concentrations of COMPOUND_XXX were slightly to moderately higher at 20:00 , 23:00 and 08:00 than at the other time points , whereas PAG concentrations were generally in a similar range within each group at all time points with the exception of an increased value for the high - dose animals at 05:00 a.m. COMPOUND_XXX plasma concentrations were higher at night and in the early morning ( 23:00 , 02:00 and 05:00 ) than at the other time points in both dose groups , which corresponds to the main activity phase of the animals .
The slight increase in serum calcium at the highest dose of 500 μg / kg COMPOUND_XXX in male animals on days 10 ( p < 0.05 ) , 17 ( n. s. ) and 24 ( n. s. ) and in female animals on days 17 ( n. s. ) and 24 ( n. s. ) is a consequence of the pharmacological action of the compound intervening in the calcium metabolism .
COMPOUND_XXX ( Batch no. 0351002 ) was administered orally by gavage as solutions in 0.5 % ( w / v ) hydroxypropylmethylcellulose ( 0.5 % HPMC ) Type E4M Premium , aqueous solution to three groups ( 10 / sex / group ) of IGS Wistar Hannover Crl : WI ( Glx / BRL / Han ) IGS BR rats at doses of 6/6 .4 , 20/21 and 60/64 mg / kg / day ( base / salt ) for at least 4 weeks .