2-amino-5-methylthiazole

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-amino-5-methylthiazole

EC Number:

423-800-5

EC Name:

2-amino-5-methylthiazole

Cas Number:

7305-71-7

Molecular formula:

C4 H6 N2 S

IUPAC Name:

5-methyl-1,3-thiazol-2-amine

Test animals

Species:

rat

Strain:

other: Chbb:THOM (SPF)

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% Natrosol 250 HX® (Hydroxyethykellulose)

Results and discussion

Effect levels

Key result

Dose descriptor:

other: NOTEL

Effect level:

4 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The 4 weeks oral administration of AMTH to albino rats resulted in a marked lowering of the thyroid function (hypothyroidism) in the animals
treated with 100 mg/kg, indicated also in the 20 mg/kg group. The changes normalized largely within the treatment-free recovery period.
Taking in aeeount all the findings mentioned above the NOTEL (No observed toxie effeet level) in the present trial is 4 mg/kg.

Executive summary:

Objective:

The aim of this study was to assess the speetrum of side-effeets, to identify target organs and to estimate the no toxie effect level of AMTH, a starting material of Meloxicam (UH-AC 62 XX), following repeated oral administration of graduated doses to rats. This investigation was required by law (Chemikaliengesetz [Chemical act], 2nd amendment of July 29, 1994).

Design of the study: Four weeks administration of AMTH suspended in hydroxyethylcellulose (Natrosol 250 HX) in dosages of 0 (control; Natrosol, GO), 4 (G 1), 20 (G 2) and 100 mg/kg (G 3) to 5 Wistar rats per dose and of eat:h sex via gastric tube. In the control and the high dose group, 5 m/5 f animals were additionally inserted for a 2 weeks recovery period, prolonged to 0 weeks during the study.

Materials and methods:

Test compound: AMTH (2-Amino-5-Methylthiazol), batch no. 141038

Anirnals: 60 rats (30 males, 30 females), Chbb:Thom (SPF)

Age at study start: 43 days

Body weight at study start: males 208.6-231.0 g, females 100.1-178.8 g

Study period: May 14-July 22, 1996

Main results:

No animal died during the study. Sedation was observed in the 20 and 100 mg/kg treated animals, in the latter one initially with prone position and dacryorrhea. The high dose (100 mg/kg) rats showed additionally rough eoat during the entire administration period. All symptoms disappeared during the recovery period. Body weight gain and food t:onsumption were decreased in the high dose group (100 mg/kg) during the administration period. In the mid dose group, the food intake was slightly lowered in the first administration week.

Changed hematological values in males and/or females were evident mainly in the high dose group in form of decrease in hemoglobin, erythrocyte count, hematocrit, reticulocytes, total leucocyte count (especially lymphocytes) and thrombocyte count. The thromboplastin time was elevated. Erythrocytes were also decreased in the 20 mglkg females. Among the clinical chemistry parameters ofthe high dose (100 mg/kg) group, slightlyelevated values were observed in LAP, bilirubin (males), total cholesterol, cholinesterase (males), BUN, creatinine and total protein (albumin and globulin). Glucose, total glycerol (males) and inorganic phosphate levels were slightly decreased in this group. All changed hematological and clinical chemistry values were largely normal after the 6 weeks treatment-free recovery period. Organ weight changes were mainly observed in the high dose group (100 mglkg). Weight decrease occurred in heart, thymus (also the 20 mglkg males), spleen, and adrenals (females only) and was of mild character. Strong weight increase was evident in thyroids. Lungs and pituitary of the high dose males were slightly elevated in weight. Apart from sporadic spontaneous changes, there were no gross pathological findings evident among the substancetreated grou ps. Test substance-related histopathological organ changes were found in the thyroid, pituitary, adrenals, thymus, liver, spleen and lungs of animals of the mid (20 mglkg) and high dose (100 mglkg) group. The macroscopically enlarged thyroids showed diffuse hypertrophy and hyperplasia of the follicle epithelium with reduced colloid content as the typical picture of hypothyroidism. This change disappeared during recovery period. At this time point, the organ showed a hyperactive appearance. The acidophilic-to-basophilic cell ratio ofthe adenohypophysis was inverted. The adrenal cortex of the high dose males was slightly atrophic. The thymus showed premature involution with reduction of all cell populations. In the lungs slightly increased foam cell aggregation was observed. This change was only weak and is therefore not regarded to be responsible for weight increase of this organ. Slight hypertrophy ofthe centrolobular hepatocytes was observed in high dose rats, most probably due to enzyme induction. The splenic red pulp was collapsed because of depletion of blood cells.