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Morphology of the cerebral cortex was studied in fetuses on gestational Day 21 following oral administration of several doses of ethanol (for total doses of 10, 15, or 18 g/kg) to pregnant rats on gestational Days 14 and 15, a critical period for the development of the cerebral cortex. All doses of ethanol were associated with a reduction in maternal weight gain, fetal body weight, and placental weight. Only the high dose of ethanol (total dose 18 g/kg) caused significant fetal cortical thinning. Acute exposure of pregnant rats to ethanol produced dose-dependent malformations of the cerebral cortex and hippocampus in fetuses. On gestational Day 21, the 18 g/kg group contained fetuses with severely disorganized cortical architecture, heterotopias of the cerebral cortex, pia and choroid plexus, and status verrucosus deformis. Fetuses from the 10 g/kg group had less severe malformations, such as disorganization of layers of cortical neurons and dentate granule cells while fetuses from the 15 g/kg group had a mixture of severe and minor malformations. This study demonstrates that acute ethanol exposure during a critical period of development in rats can result in brain malformations similar to those reported in human fetuses and neonates from alcoholic mothers.

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Cerebral cortical morphology and early motor development were evaluated in offspring from ethanol-exposed mothers, pairfed control mothers and ad libitum control rats. Ethanol-exposed rats received a total dose of 18 g/kg of ethanol by intubation on gestational Days 14 and 15, a critical period of development of the cerebral cortex. Pairfed control mothers received isocaloric sucrose on gestational Days 14 and 15 and were pairfed to ethanol-exposed animals from gestational Day 12 through gestational Day 20. Ethanol-exposed offspring weighed significantly less than control offspring from postnatal Day 7 through postnatal Day 28. Ethanol-exposed offspring also showed significant delays in reflex suspension (time an animal maintained its grip on a crossbar) and continuous corridor (number of turns in 5 min). The thickness of the cerebral cortex of ethanol-exposed offspring was significantly different from ad libitum and pairfed control offspring on postnatal Day 1. However, only Layer V and total cortical thickness were affected in ethanol-exposed offspring on postnatal Day 28. The results of this study indicate that ethanol exposure during a critical period of development causes alterations in central nervous system development and developmental delays.

Studies were conducted to evaluate the subchronic and developmental toxicity of Ac-Di-Sol (croscarmellose sodium). In the subchronic study, groups of Sprague-Dawley rats (20/sex/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet for 90 consecutive days (equivalent to 757 and 893 mg/kg/day for males and females fed 10000 ppm, respectively, and to 3922 and 4721 mg/kg/day for males and females fed 50000 ppm, respectively). No mortality, clinical signs of toxicity, or adverse toxicological effects on hematology or serum chemistry parameters, feed consumption, or ophthalmologic examinations were noted in any treatment group. Body weight gain was depressed in high-dose males during the final 3 weeks. The only treatment-related histological lesion noted was moderate renal mineralization at the corticomedullary junction in one high-dose female. This lesion was not considered a specific effect of Ac-Di-Sol, but rather a secondary effect resulting from a potential increase in urinary pH and renal excretion of sodium due to the high intake of sodium associated with Ac-Di-Sol. In the developmental toxicity study, groups of pregnant Sprague-Dawley rats (25/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet on gestational days 6 to 15. No evidence of maternal, fetal, or embryo toxicity was noted. The no-observed-adverse-effect level (NOAEL) for Ac-Di-Sol in both studies exceeds 50000 ppm in the diet, which represents doses of 3922 and 4712 mg/kg/day, for males and females, respectively. The results of these studies demonstrate the low subchronic oral toxicity and developmental toxicity of Ac-Di-Sol, and support the safe use of Ac-Di-Sol in oral applications such as pharmaceuticals, dietary supplements, and sweetener tablets.