Tissue storage after repeated administration of an HES solution with a low molar substitution (0.4) was significantly lower in the total body as well as in the liver and carcass compared with an HES solution with a medium molar substitution (0.5). However, the potential clinical consequences of these present findings have not yet been determined.

A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies. Regulatory authorities classify these secretomes as biological medicinal products, and non- clinical safety assessment thus falls under the scope of ICH S6. A secretome of stressed peripheral blood mononuclear cells (APOSEC) was successfully tested in a toxicology program, supporting clinical use of the new drug candidate. Here, to allow for topical, dermal treatment of patients with diabetic foot ulcer, several non-clinical safety studies were performed. Acute toxicity (single dose) and neuropharmacological screening were tested intravenously in a rat model. Risk for skin sensitisation was tested in mice. A 4-week intravenous toxicity study in mice and a 4-week subcutaneous toxicity study in minipigs were conducted to cover the clinical setting and application in a rodent and a non-rodent model. Acute and repeated-dose toxicity studies show that APOSEC administered intravenously and subcutaneously does not involve major toxicities or signs of local intolerance at levels above the intended total human maximal dose of 3.3 U/kg/treatment, 200 U/wound/treatment, and 100 U/cm 2 /treatment. The non-clinical data support the safe topical use of APOSEC in skin diseases related to deficient wound healing.

The "in-vivo'-toxicity of the Vanadium-oxides V20 5 and V203 (administered orally, dermally and by inhalation) has been reinvestigated with particular emphasis on the safety and handleability of vanadium-oxides in the vanadium processing industry. Chemical-thermodynamic properties of vanadium-oxides make it likely that some earlier results on vanadium-toxicities have introduced artefacts as a consequence of the administration-techniques used. Special precautions have therefore been taken to avoid any chemical changes or artificial interactions during sample-preparation to ensure that the results significantly reflect the toxicities of the vanadium-compounds as exposure to them might occur. The LDs0(14d)-values indicate, that V20 5 should be classified as "hamful" (V20 5 techn, grade fused oral LDso(14d): 716 mg/kg b.w. (rats m.) resp. 658 mg/kg b.w. (rats f.); inhal. LCs0 16.2mg/l (rats m.) resp. 4.0rag/1 (rats f.) for a 4-hour exposure), while V20 3 should be classified as "relatively non toxic" (V20 3 tech. grade powder oral: LDso(14d): 5639mg/kg b.w. (rats f.) resp. 8713 mg/kg b.w. (rats m.)) according to the EEC-commission directive of July 29, 1983 (83/467/EEC). Based on interaction-studies and considering new results reported in literature, a 3-level-model of the mechanism of vanadium-toxicity via oxygen-radicals is suggested. Neue Untersuchungen zur akuten Toxizit/it yon VanadiumoxidenZusammenfassung. Die "in-vivo"-Toxizit~it der Vanadium-Oxide V205 und V203 bei oraler, dermaler und inhalativer Applikation wurde neu untersucht. Aufgrund einer Analyse der chemisch-thermodynamischen Eigenschaften dieser V-Oxide wird nahegelegt, dab die Resultate einiger frtiherer Toxizit/itsuntersuchungen durch chemische VerS.nderungen der zu untersuchenden Stoffe bei der Probenvorbereitung verf/ilscht wurden. Nach den in-vivo-LDso(14d)-Werten ist V20 5 als "mindergiftig" (V20 5 techn. "fused" oral LDso(14d): 716 mg/kg b.w. (Ratten m.) bzw. 658 mg/kg b.w. (Ratten w.); inhalotiv LCso 16.2 mg/1 (Ratten m.) bzw. 4.0 mg/1 (Ratten w.) for a 4-hour exposure) bzw. V20 3 (techn. pulv. peroral LDso(14d): 5639 mg/kg KG (Ratten w.) bzw. 8713 mg/kg KG (Ratten m.) als relativ nicht toxisch-nicht klassifiziert gem~13 EEC-Commission-Directive vom 29. Juli 1983 (83/467/EEC) einzustufen. Basierend auf Studien der Interaktionswirkung bestimmter Substanzen und unter Eibeziehung der Resultate jtingst mitgeteilter Befunde zur Vanadium-Toxizit~t an Zellkulturen, wird ein ModelI zum Vanadium-Toxizitfits-Wirkungsmechanismus vorgeschlagen, das 3 Hauptmechanismen -abh/ingig yon der Konfrontations-Intensitfit (Konzentration und Expositionsdauer) -nahelegt.

No abstract

The toxicity of articaine (CAS 23964-58-1) and of a respective preparation (Septanest SP; 4% articaine HCl and epinephrine 1: 100,000) was examined in in vitro and in vivo experiments. The following endpoints were examined: repeated dose toxicity, reproduction toxicity, mutagenic potential and local tolerance. Repeated s.c. administration of articaine HCl in rats and dogs demonstrated no pathomorphological systemic changes even at systemically toxic doses. The no-effect level (NOEL) was 25 mg articaine HCl/kg b.w./day s.c. for the rat and 40 mg articaine HCl/kg b.w./day s.c. for the dog. Reproduction studies were performed in rats and rabbits at doses up to more than 10 times the maximum recommended human dose of 7 mg articaine HCl/kg b.w. and revealed no evidence of harm to the foetus or to other aspects of reproduction, even at doses toxic to the parental animals. Four standard in vitro and in vivo mutagenicity studies have shown no mutagenic potential up to cytotoxic concentrations or up to the maximum tolerated dose level. The local tolerance of articaine HCl was good to very good. The preclinical data indicate that articaine HCl does not possess any relevant side-effects or gross toxicity and can be considered a safe local anaesthetic.