benzalazine and Weight-Gain

Benzalazine (2-hydroxy-5-[(4carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated regarding its toxicological properties following single and subacute local and systemic applications. After single oral application of the maximum dose of 10 g benzalazine/kg b.w. to rats no pathological findings concerning clinical signs, body weight, food consumption and macroscopical post mortem findings could be observed (LD50 > 10000 mg/kg b.w.). The 24-h LD50 values for benzalazine after single intraperitoneal application were determined as 755 mg/kg b.w. in female rats and 1200 mg/kg b.w. in male rats. The oral administration of benzalazine at 2000 mg/kg b.w./d or more for 4 weeks to rats gave rise to slight sedation, a reduction in body weight increase, increased organ weights (heart, kidneys, suprarenal glands, spleen) and dose-related histopathological findings (liver, kidneys, heart, thyroid gland, duodenum, spleen, suprarenal glands, testes). The daily dose of 500 mg benzalazine/kg b.w. for 4 weeks was without any effects under these experimental conditions. In acute local tolerance studies in rabbits, benzalazine is to be considered as a mild irritant agent for skin (employing an occlusive patch for 24 h) and eye. After a 10-day intra-rectal application of benzalazine to rabbits no substance-related changes at the application sites in the colon were observed.

Topics: Administration, Rectal; Administration, Topical; Animals; Benzaldehydes; Blood Cell Count; Blood Chemical Analysis; Eating; Eye Diseases; Female; Hydrazones; Irritants; Lethal Dose 50; Male; Organ Size; Rabbits; Rats; Rats, Wistar; Skin Tests; Weight Gain

A 26-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo] benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, as a part of a safety evaluation program. Dosages of 0 (control), 300, 900 and 2700 mg/kg b.w./d were selected for this study. Except slight changes in the urinary status (decreased pH value and increased specific gravity) from 900 mg/kg b.w./d p.o. onwards, which were probably substance related, no further intolerance reactions were observed. The urine had a dark-yellow colour which was probably an indication of metabolites of benzalazine or benzalazine itself which were excreted via the urine. Behaviour, external appearance, body weight gain, food and water consumption, haematology, clinical biochemistry, organ weight analysis, macroscopic and microscopic examinations revealed no substance-related influence. Therefore, on the basis of the results obtained, it is concluded that the non-toxic dose level in this study is considered to be 300 mg benzalazine/kg b.w./d p.o. following daily administration for 26 weeks.

Topics: Animals; Behavior, Animal; Benzaldehydes; Blood Cell Count; Blood Chemical Analysis; Drinking; Eating; Eye Diseases; Female; Hearing Disorders; Hydrazones; Male; Rats; Rats, Sprague-Dawley; Tooth; Urinalysis; Weight Gain

The 26-week oral toxicity of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated in beagle dogs of both sexes. No change was observed in the 160 mg/kg group. A reduction of the aspartate aminotransferase activity was observed from 800 mg/kg b.w./d onwards. In high-dosed dogs (1600 mg/kg b.w./d) liver weights were increased and substance-related neutral fat disposition in liver cells was observed. The non-toxic dose was 160 mg/kg b.w./d under these experimental conditions.

Topics: Animals; Behavior, Animal; Benzaldehydes; Blood Cell Count; Blood Chemical Analysis; Blood Protein Electrophoresis; Dogs; Eating; Eye Diseases; Female; Hearing Disorders; Hydrazones; Male; Organ Size; Weight Gain

Embryotoxicity studies of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were performed in rats and rabbits. Benzalazine elicited no evidence of teratogenicity when administered orally during the fetal organogenesis period to pregnant rats at doses up to 2000 mg/kg b.w./d, or to pregnant rabbits at doses up to 1000 mg/kg b.w./d. Rat fetuses in the 400 and 2000 mg/kg groups exhibited decreased body weights; the placentae weights were decreased in these dose groups, too. Rabbit fetuses in the high-dose group (1000 mg/kg b.w./d p.o.) also showed decreased body weights. Decreased body weight gain and reduced food intake were seen in rat dams in the high-dose group (2000 mg/kg b.w./d p.o.). In rabbit dams a decrease in body weight gain in the high-dose group (1000 mg/kg b.w./d p.o.) and a dose-dependent reduction in food intake from 200 mg/kg b.w./d p.o. onwards were noted. No further disturbances were observed in the behaviour of the rat and rabbit dams. External appearance, faeces, consumption of drinking water and macroscopical inspection during autopsy did not indicate any influence of the test compound. No retardations or malformations were seen even at the highest tested dose levels (rat: 2000 mg/kg b.w./d p.o.; rabbit: 1000 mg/kg b.w./d p.o.).

Topics: Animals; Behavior, Animal; Benzaldehydes; Body Weight; Eating; Embryo, Mammalian; Embryonic and Fetal Development; Female; Hydrazones; Male; Pregnancy; Rabbits; Rats; Rats, Wistar; Reproduction; Teratogens; Weight Gain

Oncogenicity studies of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were carried out in male and female mice and rats. The compound was administered in the diet for 119 weeks (rats) and 120 weeks (mice) at dose levels of 100, 300 and 900/1800 mg/kg b.w./d for mice and of 300, 900 and 2700/1800 mg/kg b.w./d for rats. The administration of benzalazine produced no effects on survival, appearance or behaviour. Body weights of the high-dosed male mice and rats (both sexes) were occasionally significantly decreased when compared to the controls. A slight but in most cases statistically significant reduction of the relative food consumption of the female mice of all treated groups was observed between test weeks 6 and 12. In the high-dosed rats a statistically significant increase of the relative food consumption was found between test weeks 17 and 109. At necropsy, there was no evidence of treatment-related changes, nor were these seen on histopathological examination. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged NMRI mice and Sprague-Dawley rats. However, an increased incidence of thyroid cystic hyperplasia was found in the rats of the high dose-level group. In addition, an increased incidence of thyroid adenomas was found in the male rats of the high-dosed group only as compared to the control groups. This increased tumour incidence is regarded as a marginal finding and may be of a spontaneous nature within the normal range of the background data. However, a substance-related influence cannot completely be excluded. In conclusion, the administration of benzalazine for more than 24 months to NMRI mice and Sprague-Dawley rats produced only slight effects on body weight in the high-dosed male mice and in rats (both sexes) with a no-effect level of 300 mg/kg b.w./d in the diet for mice or 900 mg/kg b.w./d in the diet for rats. There was no evidence of an oncogenic effect of benzalazine.

Topics: Adenoma; Animals; Benzaldehydes; Carcinogenicity Tests; Carcinogens; Eating; Female; Hydrazones; Hyperplasia; Male; Mice; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyroid Neoplasms; Weight Gain