13-week oral toxicity study of vinyl laurate in rats.

Vinyl laurate (VL) is used as a monomer in the production of polyvinyl acetate vinyl laurate copolymer, a component of chewing gum base. The safety of VL was examined in a 13-week oral toxicity study in Wistar rats. VL was administered in corn coil by daily gavage (5 ml/kg bw/d) to four main groups (10 rats/sex) at doses of 0 (vehicle only), 50, 250 and 1000 mg/kg bw/d, respectively. The control and high-dose group comprised an additional 5 rats/sex which were kept untreated for a further 4 weeks until sacrifice (recovery groups). In addition to standard parameters, male and female fertility parameters were determined as well. There were no mortalities and treatment-related clinical signs. Neurobehavioral observations and motor activity assessment, ophthalmoscopic examinations, body weights, feed and water intakes, blood cell counts, coagulation time, standard clinical chemical parameters and urinalyses, absolute and relative organ weights at the end of the treatment as well as macroscopic examination at necropsy and microscopic examination of standard organs and tissues did not show any treatment-related changes. Female and male fertility parameters (estrus cyclicity, testicular and epididymal sperm counts, sperm motility and morphology) were not affected by the treatment. Accordingly, the no-observed-adverse-effect level (NOAEL) for VL was determined to be 1000 mg/kg bw/d, i.e. the highest dose level tested.

Safety evaluation of pectin-derived acidic oligosaccharides (pAOS): genotoxicity and sub-chronic studies.

Pectin-derived acidic oligosaccharides (pAOS) are non-digestible carbohydrates to be used in infant formulae and medical nutrition. To support its safety, the genotoxic potential of pAOS was evaluated. pAOS was not mutagenic in the Ames test. Positive results were obtained in the chromosome aberration test only at highly cytotoxic concentrations. The effects obtained in the mouse lymphoma test were equivocal; pAOS was not mutagenic in vivo. A sub-chronic dietary study, preceded by 4-week parental and in utero exposure phase, investigated general safety. Administration of pAOS did not affect parental health nor pup characteristics. No effects specific for acidic oligosaccharides were observed in the subsequent sub-chronic study. Slight diffuse hyperplasia of epithelial layer of the urinary bladder was noted to result from concurrently elevated urinary sodium, due to high sodium in pAOS, and elevated urinary pH. This phenomenon was confirmed in a mechanistic (sub-chronic) study. In contrast, in rats fed pAOS in combination with NH(4)Cl, an acidifying agent, the induced low urinary pH completely prevented the development of urothelial hyperplasia. Hyperplasia induced by this mechanism in rats is considered not relevant to man. Based on the current knowledge we consider pAOS safe for human consumption under its intended use.

Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.

As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans.