Reproductive toxicity studies of ademetionine.

S-Adenosyl-L-methionine sulphate-p-toluene sulphonate (ademetionine, SAMe), a donor of methyl groups, was examined for effects upon embryofoetal toxicity following both premating treatment and treatment during pregnancy and for peri- and post-natal toxicity in the rat at dosages of 0, 100, 200 and 400 mg/kg/d SAMe ion by subcutaneous or intravenous administration. Embryofoetal toxicity was also examined in the New Zealand White rabbit at dosages of 0, 10, 20 and 40 mg/kg/d SAMe by intravenous administration. Treatment was considered to be without adverse effect upon any of the reproductive parameters examined on either F0 or on the untreated F1 generations. There was no indication that treatment adversely affected the litter parameters including the incidences of malformations, anomalies and skeletal variants. Some slight changes in the activity of the F1 females derived from F0 animals given 400 mg/kg/d were considered to be of minimal importance. In contrast to the above, adverse effects upon the parents were noted at 400 mg/kg/d including local tissue reaction at the injection sites and retardation of body weight gain. In the intravenous studies some rigidity and dyspnoea were noted following administration. Following subcutaneous premating treatment there was also evidence of histopathological change to the kidney of the female rat. Increased water consumption was noted in this latter study and amongst females rearing offspring in the embryo foetal toxicity study in which the compound was administered intravenously. At the lower dosages administered to the rat some local tissue reaction was evident as was some retardation of body weight gain, minimal at the lowest intravenous dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive toxicity studies of rentiapril.

(2R,4R)-2-(o-Hydroxyphenyl)-3-(3-mercaptopropionyl)-4- thiazolidinecarboxylic acid (rentiapril, SA 446), an orally active inhibitor of angiotensin converting enzyme, was examined for effects upon general reproductive performance, for embryofoetal toxicity and for peri- and postnatal toxicity in the rat at dosages of 0, 20, 100 and 500 mg/kg/d. Embryofoetal toxicity was also examined in the New Zealand White rabbit at dosages of 0, 1, 2 and 4 mg/kg/d. The compound was administered by gastric intubation. Prolonged treatment at 100 and 500 mg/kg/d during the fertility study was associated with some slight depression of body weight gain of males. Body weight gain of females during gestation was significantly depressed at 500 mg/kg/d. There was salivation in both sexes at 500 mg/kg/d and also in males receiving 100 mg/kg/d. Following this prolonged treatment in the fertility study. Fo male and female kidney weights were increased at all dosages. Although there was no obvious effect upon fertility there was an increased incidence of total litter loss at 500 mg/kg/d and mean pup weights to day 21 post partum were reduced at this dosage and at 100 mg/kg/d with delays in the attainment of some of the developmental landmarks. In the rat treatment at 500 mg/kg/d from day 7 to 17 of pregnancy did not adversely effect embryofoetal development. Subsequent development and reproductive performance of the F1 offspring was also unimpaired. During this treatment period signs of salivation were seen at 500 mg/kg/d. Slight retardation of maternal body weight gain was noted at 500 mg/kg/d and at 100 mg/kg/d but not at 20 mg/kg/d.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant mastocytoma in mice.

Four cases of spontaneous malignant mastocytoma were found in some 20 000 mice. Only liver and spleen were involved in one case, but there was widespread dissemination in the three other animals. Involvement of peripheral blood was detected in only one mouse. In all cases the neoplastic cells were well differentiated, with abundant metachromatic granules.

The effect of lentinan on fertility and general reproductive performance of the rat.

Lentinan, a polysaccharide [(1 leads to 3)-beta-D-glucan], at 0.01, 0.10 or 1.0 mg/kg/day, was administered i.v. once daily to male rats for 9 weeks and to females for 2 weeks before mating. Some animals continued to be treated until they were killed during gestation: others were killed on day 21 post partum. Selected animals of the F1 generation were retained without further treatment, to provide F2 offspring. Reactions to treatment were generally dose-related and included bruising and cutaneous lesions of the tail and swelling and discolouration of the pinnae. In males given 1.0 mg/kg/day there was a clear evidence of gonadal damage and impairment of reproductive capacity; this effect was less marked at 0.1 mg/kg/day and much reduced at 0.01 mg/kg/day. However, the reproductive performance of the selected F1 pups did not appear to have been affected by the treatment of the F0 parents at any dosage. In animals of both sexes there was a dose-related enlargement of the spleen, with evidence of macrophage infiltration.

The effect of lentinan on the in utero foetal development of the rat and on postnatal development of the F1 offspring.

Lentinan, a polysaccharide [(1 leads to 3)-beta-D-glucan], at 0.1, 1.0 and 5.0 mg/kg/day was administered i.v. to rats once daily from day 15 of pregnancy to day 21 post partum. All animals were allowed to deliver their young and selected animals of the F1 generation were retained without further treatment, to provide F2 offspring. Reactions to treatment were generally dose-related and included bruising of the tail and swelling and discolouration of the pinnae. Animals at 5.0 mg/kg/day sometimes showed swollen hind limbs and cutaneous lesions of the tail. Mean spleen weight in females was increased at all dosages, more so at 1.0 and 5.0 mg/kg/day. There was no evidence of an adverse effect on litter characteristics, including the pre-weaning development of the F1 offspring, or that treatment of the F0 parents adversely affected post-weaning development and reproductive performance of the F1 offspring.

The effect of lentinan on the in utero embryonic and foetal development of the rat and on postnatal development of the F1 offspring.

Lentinan, a polysaccharide [(1 leads to 3)-beta-D-glucan], at 0.10, 1.0 or 5.0 mg/kg/day was administered i.v. to rats once daily from day 6 until, and including, day 17 of pregnancy. Some animals were killed on day 20 of gestation, others were killed on day 21 post partum. Selected animals of the F1 offspring were retained without further treatment, to provide F2 offspring. Reactions to treatment were generally dose-related and included swelling and discolouration of the pinnae, with occasional cutaneous lesions of the tail and swelling of the hind feet. Spleen weight was increased at all dosages. Litter characteristics at day 20 of pregnancy, including the incidence of abnormality, were not affected by treatment. For dams allowed to litter, mean pup weights were slightly increased, with slight acceleration of some physiological markers before weaning. There was no evidence that treatment of the F0 parents affected the reproductive performance of the F1 offspring.

Intraocular melanoma in the rat.

8 cases are reported of intraocular melanoma encountered in treated and untreated rats from 6 chronic toxicity studies.