Internationalization of read-across as a validated new approach method (NAM) for regulatory toxicology.

Read-across (RAx) translates available information from well-characterized chemicals to a substance for which there is a toxicological data gap. The OECD is working on case studies to probe general applicability of RAx, and several regulations (e.g., EU-REACH) already allow this procedure to be used to waive new in vivo tests. The decision to prepare a review on the state of the art of RAx as a tool for risk assessment for regulatory purposes was taken during a workshop with international experts in Ranco, Italy in July 2018. Three major issues were identified that need optimization to allow a higher regulatory acceptance rate of the RAx procedure: (i) the definition of similarity of source and target, (ii) the translation of biological/toxicological activity of source to target in the RAx procedure, and (iii) how to deal with issues of ADME that may differ between source and target. The use of new approach methodologies (NAM) was discussed as one of the most important innovations to improve the acceptability of RAx. At present, NAM data may be used to confirm chemical and toxicological similarity. In the future, the use of NAM may be broadened to fully characterize the hazard and toxicokinetic properties of RAx compounds. Concerning available guidance, documents on Good Read-Across Practice (GRAP) and on best practices to perform and evaluate the RAx process were identified. Here, in particular, the RAx guidance, being worked out by the European Commission's H2020 project EU-ToxRisk together with many external partners with regulatory experience, is given.

Ecotoxicities of polyquaterniums and their associated polyelectrolyte-surfactant aggregates (PSA) to Gambusia holbrooki.

The toxicity of 11 polyquaterniums used in cosmetic applications, and polydimethyldiallylammonium chloride (poly(DADMAC)) were studied for toxicity of the polyquaternium alone, and of a polyquaternium/anionic surfactant complex as occurs in some cosmetic formulations. The surfactant used in the study was sodium dodecyl sulfate (SDS), which is used in cosmetic formulations under its International Nomenclature of Cosmetic Ingredients (INCI) name Sodium Laurel Sulfate. In fish immobilization studies with Gambusia holbrooki, the EC(50) of the polyquaternium/surfactant complex was found to be the same as or similar to the EC(50) for the polyquaternium alone. The toxicity of the polyquaterniums investigated was similar to the published values for other cationic polyelectrolytes and cationic surfactants, in the range from < 1.0 to 10 mg/L, with the exception of low charge density cellulosic polyquaterniums. The anionic surfactant alone was not toxic to fish in the concentration range tested. Results thus showed the toxicity of the polyquaternium was not mitigated by the presence of the anionic surfactant.

X-ray Crystallographic Study of the Ruthenium Blue Complexes [Ru(2)Cl(3)(tacn)(2)](PF(6))(2).4H(2)O, [Ru(2)Br(3)(tacn)(2)](PF(6))(2).2H(2)O, and [Ru(2)I(3)(tacn)(2)](PF(6))(2): Steric Interactions and the Ru-Ru "Bond Length"

X-ray crystal structures are reported for the following complexes: [Ru(2)Cl(3)(tacn)(2)](PF(6))(2).4H(2)O (tacn = 1,4,7-triazacyclononane), monoclinic P2(1)/n, Z = 4, a = 14.418(8) Å, b = 11.577(3) Å, c = 18.471(1) Å, beta = 91.08(5) degrees, V = 3082 Å(3), R(R(w)) = 0.039 (0.043) using 4067 unique data with I > 2.5sigma(I) at 293 K; [Ru(2)Br(3)(tacn)(2)](PF(6))(2).2H(2)O, monoclinic P2(1)/a, Z = 4, a = 13.638(4) Å, b = 12.283(4) Å, c = 18.679(6) Å, beta = 109.19(2) degrees, V = 3069.5 Å(3), R(R(w)) = 0.052 (0.054) using 3668 unique data with I > 2.5sigma(I) at 293 K; [Ru(2)I(3)(tacn)(2)](PF(6))(2), cubic P2(1)/3, Z = 3, a = 14.03(4) Å, beta = 90.0 degrees, V = 2763.1(1) Å(3), R (R(w)) = 0.022 (0.025) using 896 unique data with I > 2.5sigma(I) at 293 K. All of the cations have cofacial bioctahedral geometries, although [Ru(2)Cl(3)(tacn)(2)](PF(6))(2).4H(2)O, [Ru(2)Br(3)(tacn)(2)](PF(6))(2).2H(2)O, and [Ru(2)I(3)(tacn)(2)](PF(6))(2) are not isomorphous. Average bond lengths and angles for the cofacial bioctahedral cores, [N(3)Ru(&mgr;-X)(3)RuN(3)](2+), are compared to those for the analogous ammine complexes [Ru(2)Cl(3)(NH(3))(6)](BPh(4))(2) and [Ru(2)Br(3)(NH(3))(6)](ZnBr(4)). The Ru-Ru distances in the tacn complexes are longer than those in the equivalent ammine complexes, probably as a result of steric interactions.