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The current study investigated the influence of ethanol and ethanol-containing mouthrinses on model chemical permeability in an in vitro oral buccal mucosal construct (EpiOral, ORL-200, MatTek). Innate ethanol transport and metabolism in the tissue construct was also studied. Caffeine flux in buccal tissue was measured after pre-treatment with < 26.9% ethanol or Listerine(®) products under conditions modeling a typical mouthwash rinsing. Specifically, a 30s exposure to alcohol products followed by a 10h non-treatment phase and then a second 30s exposure prior to addition of caffeine. At 10min specific intervals, media was collected from the basal part of the tissue insert for HPLC analysis of caffeine. The results demonstrated no increase in caffeine flux due to prior exposure to either ethanol or Listerine(®), and the flux and permeability constants were derived from the linear phase. No cytotoxicity or histopathological effects were observed in these tissues. We also studied the transepithelial transport and metabolism of ethanol in these tissues. Transport of ethanol was concentration-dependent with rate of diffusion proportional to the concentration gradient across the membrane. The potential metabolism of ethanol in the EpiOral construct was addressed by analyzing the remaining level of ethanol after incubation and de novo accumulation of acetaldehyde or acetic acid in culture media. Incubation for 30min incubation resulted in no change in ethanol level up to 2000mM, the highest concentration tested. No acetaldehyde or acetic acid was detected in culture media. In conclusion, ethanol and ethanol-containing mouthrinse treatment modeled after a typical daily mouthrinse pattern had no apparent effect on the permeability of the standard model chemical, caffeine. This exposure also had no effect on the viability of the tissue construct or histopathology, and uptake of ethanol was rapid into the tissue construct., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

TBA, or 2,4,6-tribromoanisole, is a musty-smelling metabolite of 2,4,6-tribromophenol that is used as a flame retardant and an antifungal agent for wooden pallets and packaging materials. The compound can impart its peculiar, often offensive, odor on product packaging to the concern of consumers for the safety of the package contents. These studies were conducted to evaluate the safety of TBA to humans ingesting products tainted with TBA. In addition to the 28-day oral study, a bacterial reverse mutation study was conducted, and confirmed that TBA was not mutagenic. To evaluate oral safety, TBA was evaluated in single dose and 5-day and 4-week repeated dose oral toxicity studies in rats. The test article, administered in single gavage doses of 2000, 5000 and 7500 mg/kg body weight (bw), in 5 daily repeated doses of 1000, 2000 or 3000 mg/kg bw/day or in 28 daily oral gavage doses of 0 001, 0.01, 100, and 1000 mg/kg bw/day did not result in any deaths. Also, the single and repeat dose studies resulted in no significant differences between control and treated groups on body weight gain, food consumption, clinical observations, blood biochemical values, and hematology findings. Treatment-related adverse findings were only detected in male rats during repeated dose studies and were associated with high plasma concentrations of TBA. The test article-related finding of hyaline droplets in the cortical tubular epithelium of kidneys was associated with increases in α(2 μ)-globulin content in the kidneys as indicated by the intensity of immunohistochemical staining. These findings were correlated with an increased weight of kidneys in males administered 1000mg/kgbw/day for 28days. Chemical induction of hyaline droplets containing α(2μ)-globulin in the renal proximal tubule is a process unique to the male rat and is not relevant for human risk assessment. Findings of increased liver weight with minimal centrilobular to diffuse hepatocellular hypertrophy in males treated with TBA at 1000mg/kg bw/day for 28days were considered to be an adaptive metabolic response to xenobiotic administration. The increased volume of urine, noted in both males and females treated with 1000mg/kg bw/day was considered adaptive and necessary to excrete the high xenobiotic burden resulting from TBA administration. TBA appeared to be highly bioavailable since high concentrations of TBA were detected in plasma, at 1, 4 and 8h after administration of TBA at 100 and 1000mg/kg bw for 1 and 28days. Levels were dose-related but did not clarify the course of TBA elimination with time after administration. These studies indicate that TBA, administered orally to rats, produced male rat-specific, treatment-related toxicity at the highest orally administered dose in repeated dose (5-day at 3000mg/kg bw and 28-day at 1000mg/kg bw) studies. Therefore, the NOAEL for the 28-day oral study was determined to be 1000mg/kg bw/day for the rat., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Completing a SAR study, a series of (RS)-1- or 3-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-pyrimidines and (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H- or 9H-purines have been prepared. Their antiproliferative activities on MCF-7 cells are here presented and discussed. (RS)-6-Chloro-9-[1-(9H-9-fluorenylmethoxycarbonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]-9H-purine (28) is the most active (IC(50)=0.67+/-0.18 microM) of the series so far described. cDNA microarray technology reveals potential drug targets, which are mainly centred on apoptosis regulatory pathway genes.

Ten new structures of a series of the title compounds were synthesized and screened for their activity to inhibit choline kinase under ex vivo conditions. Their inhibitory potency correlates with the 13C chemical shifts (in CD3OD) of the methylene group bearing the positively charged nitrogen. The inhibitory effect on proliferation against the HT-29 cell line is strongly dependent on its ability to inhibit the production of phosphorylcholine.

The effect of feeding Welch's Special Grape Color Powder Type BW-AT at dose levels of 7.5 and 15% w/w in the diet for 90 days was studied in beagle dogs. Body-weight gain of male and female dogs at the high dose level was significantly decreased compared with control dogs. No other treatment-related effects were seen in food consumption, haematology, clinical chemistry, ophthalmology or gross and histopathological findings.

The effect of Welch's Special Grape Color Powder Type BW-AT on reproductive performance was studied through two generations of Sprague-Dawley rats and a subchronic study was carried out on the F1 animals. The grape colour powder at dietary levels of 7.5 and 15.0% (w/w) had no adverse effects on reproductive performance. Body weights for F0 and F1 generation pups at both dose levels were significantly lower (P less than 0.05) than those of control pups at 21 days after birth. During the 13-wk subchronic feeding study of F1 rats, the body-weight gain of female rats in the high-dose group was reduced compared with the controls (P less than 0.05). Food conversion data was comparable among groups, thus the decrease in body-weight gain during this phase was most likely the result of the lower calorific value (w/w) of the feed supplemented with the grape colour powder compared with the control feed. No toxic effects or pathological changes were noted in rats fed grape colour powder.

Carnauba wax fed at levels of 0.1, 0.3 and 1% in the diet to beagle dogs for 28 wk did not produce evidence of toxicity or pathological effects. Body weight gain, food consumption, clinical chemical, haematological, and urine analysis data, and organ weights of animals fed carnauba wax were comparable with those of control animals. Ophthalmic, gross and histopathological examinations revealed no significant treatment-related findings.