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5-Aminosalicylic acid-O-sulfate (5-ASA sulfate), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated for its pharmacokinetic and toxicological properties, following local and systemic application. 5-ASA sulfate can be considered as a non-toxic agent after single oral intake in rats (14-day LD506000 mg/kg b.w.). Oral application of 2500 mg 5-ASA sulfate/kg b.w./d for 28 days to rats resulted in significantly increased body weight gain and food and water consumption. Alanine aminotransferase and alkaline phosphatase values were elevated in high-dosed (2500 mg/kg b.w./d p.o.) males. Relative liver weights were significantly increased in high-dosed males and females and the macroscopical inspection revealed thickened liver margins. The no-effect level following 28 days of oral application to rats was determined as 500 mg 5-ASA sulfate/kg b.w./d. In acute local tolerance studies in rabbits, 5-ASA sulfate is rated as non-irritant to the skin and the eye. After a single oral administration of 1800 mg 5-ASA sulfate to 5 healthy human test subjects, 5-ASA sulfate was almost completely metabolized by all test subjects within 3 days; mean urinary and faecal excretion of unchanged 5-ASA sulfate amounted to only 6.7% of the administered dose. A high faecal excretion of the active metabolite 5-aminosalicylic acid (5-ASA) (21.2% of the administered dose) and a low urinary excretion (1.4% of the administered dose) were observed.

Diperdipine (ethyl-(beta-piperidinoethyl)-2,6-dimethyl-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, CAS 149543-07-7), a new calcium antagonist, will be used for the treatment of hypertension, angina pectoris and dysrhythmic conditions. The studies conducted were carried out to evaluate the risk following oral and intravenous application of diperdipine. In accordance with the administration route envisaged for man the drug was applied by oral and intravenous administration. Studies were performed on the acute and subchronic toxicity, local tolerance and mutagenic potential. The single application of diperdipine to mice and rats by gavage caused intolerance reactions starting at the lowest tested dose level of 200 mg/kg b.w. p.o. (mice) and at 250 mg/kg b.w. p.o. (rats). After single intravenous injection intolerance reactions occurred starting at the lowest tested dose level of 10 mg/kg b.w. for mice and rats. The test substance proved to be only mildly toxic after repeated (up to 3 months) oral administration. In the rat, toxic effects occurred from 15 mg diperdipine/kg b.w./day p.o. onwards. Target organ is the liver with a miliary/submiliary hepatocellular necrosis. No mutagenic potential was observed. The therapeutic index (ratio of the toxic dose in animals and the therapeutic human dose) for oral administration of diperdipine is at least 20, for i.v. administration at least 40 depending on animal species, frequency of administration, dose levels employed and the toxicological question posed.

Medroxyprogesterone acetate (CAS 71-58-9) is used for cyclic hormone substitution during the menopause and in hormone therapy of breast cancer. The test substance was investigated for its mutagenic potential in a series of test systems according to the current EC guidelines. There were no indications for a mutagenic potential of medroxyprogesterone acetate.

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 (LD5010000 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.

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.).

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.

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.

The pharmacokinetic properties 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 investigated. From jejunal loops of rats in situ no noteworthy absorption of benzalazine was observed. All attempts to demonstrate metabolic conversion of benzalazine in mucosal homogenate of the small intestine of rats were without any success. In faecal suspensions, the half-life of the metabolic conversion of benzalazine was determined as 15 min and the formation of the metabolite 5-aminosalicylic acid (5-ASA) was demonstrated qualitatively. 72 h after single oral administration of 300 mg benzalazine/kg b.w. to rats, an average of 71.83% of the administered dose was recovered in urine and faeces. Only a small amount of unmetabolized benzalazine was excreted with urine and faeces (0.75% and 1.47% of the administered dose, respectively). The benzalazine metabolite 5-ASA and the 5-ASA metabolite acetyl-5-aminosalicylic acid (Ac-5-ASA) were excreted mainly with the faeces (29.22% and 20.66% of the administered dose, respectively) and only in small amounts with the urine (2.54% and 11.06% of the administered dose, respectively).

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 studied for genotoxic effects by using the following short-term in vitro and in vivo test: 1. reverse mutation test (Ames method) on Salmonella typhimurium, 2. HGPRT (hypoxanthine-guanine phosphoribosyl transferase) point mutation test on V79 hamster cells, 3. in vivo cytogenetic test on Chinese hamster cells, and 4. in vivo sister chromatid exchange test on Chinese hamster cells. Benzalazine did not show any positive response in the reverse mutation test, HGPRT-point mutation test, in vivo cytogenetic and sister chromatid exchange test.