Integrated in silico strategy for PBT assessment and prioritization under REACH.

Chemicals may persist in the environment, bioaccumulate and be toxic for humans and wildlife, posing great concern. These three properties, persistence (P), bioaccumulation (B), and toxicity (T) are the key targets of the PBT-hazard assessment. The European regulation for the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) requires assessment of PBT-properties for all chemicals that are produced or imported in Europe in amounts exceeding 10 tonnes per year, checking whether the criteria set out in REACH Annex XIII are met, so the substance should therefore be considered to have properties of very high concern. Considering how many substances can fall under the REACH regulation, there is a pressing need for new strategies to identify and screen large numbers fast and inexpensively. An efficient non-testing screening approach to identify PBT candidates is necessary, as a valuable alternative to money- and time-consuming laboratory tests and a good start for prioritization since few tools exist (e.g. the PBT profiler developed by US EPA). The aim of this work was to offer a conceptual scheme for identifying and prioritizing chemicals for further assessment and if appropriate further testing, based on their PBT-potential, using a non-testing screening approach. We integrated in silico models (using existing and developing new ones) in a final algorithm for screening and ranking PBT-potential, which uses experimental and predicted values as well as associated uncertainties. The Multi-Criteria Decision-Making (MCDM) theory was used to integrate the different values. Then we compiled a new set of data containing known PBT and non-PBT substances, in order to check how well our approach clearly differentiated compounds labeled as PBT from those labeled as non-PBT. This indicated that the integrated model distinguished between PBT from non-PBT compounds.

Physiological implications of the abnormal absence of the parietal foramen in a late Permian cynodont (Therapsida).

The third eye (pineal eye), an organ responsible for regulating exposure to sunlight in extant ectotherms, is located in an opening on the dorsal surface of the skull, the parietal foramen. The parietal foramen is absent in extant mammals but often observed in basal therapsids, the stem-group to true mammals. Here, we report the absence of the parietal foramen in a specimen of Cynosaurus suppostus, a Late Permian cynodont from South Africa (SA). Comparison with Procynosuchus delaharpeae, a contemporaneous non-mammalian cynodont from SA, demonstrates that the absence of this foramen is an abnormal condition for such a basal species. Because seasonality was marked during the Late Permian in SA, it is proposed that the third eye was functionally redundant in Cynosaurus, possibly due to the acquisition of better thermoregulation or the evolution of specialized cells in the lateral eyes to compensate for the role of the third eye.

Saurodesmus robertsoni Seeley 1891-The oldest Scottish cynodont.

Predating Darwin's theory of evolution, the holotype of Saurodesmus robertsoni is a long-standing enigma. Found at the beginning of 1840s, the specimen is a damaged stylopodial bone over decades variably assigned to turtles, archosaurs, parareptiles, or synapsids, and currently nearly forgotten. We redescribe and re-assess that curious specimen as a femur and consider Saurodesmus robertsoni as a valid taxon of a derived cynodont (?Tritylodontidae). It shares with probainognathians more derived than Prozostrodon a mainly medially oriented lesser trochanter and with the clade reuniting tritylodontids, brasilodontids, and mammaliaforms (but excluding tritheledontids) the presence of a projected femoral head, offset from the long axis of the femoral shaft; a thin, plate-like greater trochanter; a distinct dorsal eminence proximal to the medial (tibial) condyle located close to the level of the long axis of the femoral shaft and almost in the middle of the width of the distal expansion; and a pocket-like fossa proximally to the medial (tibial) condyle. Saurodesmus robertsoni is most similar to tritylodontids, sharing at least with some forms: the relative mediolateral expansion of the proximal and distal regions of the femur, the general shape and development of the greater trochanter, the presence of a faint intertrochanteric crest separating the shallow intertrochanteric and adductor fossae, and the general outline of the distal region as observed dorsally and distally. This makes Saurodesmus robertsoni the first Triassic cynodont from Scotland and, possibly, one of the earliest representatives of tritylodontids and one of the latest non-mammaliaform cynodonts worldwide. Moreover, it highlights the need for revisiting historical problematic specimens, the identification of which could have been previously hampered by the lack of adequate comparative materials in the past.

Collaborative decision support and documentation in chemical safety with KnowSEC.

To protect the health of human and environment, the European Union implemented the REACH regulation for chemical substances. REACH is an acronym for Registration, Evaluation, Authorization, and Restriction of Chemicals. Under REACH, the authorities have the task of assessing chemical substances, especially those that might pose a risk to human health or environment. The work under REACH is scientifically, technically and procedurally a complex and knowledge-intensive task that is jointly performed by the European Chemicals Agency and member state authorities in Europe. The assessment of substances under REACH conducted in the German Environment Agency is supported by the knowledge-based system KnowSEC, which is used for the screening, documentation, and decision support when working on chemical substances. The software KnowSEC integrates advanced semantic technologies and strong problem solving methods. It allows for the collaborative work on substances in the context of the European REACH regulation. We discuss the applied methods and process models and we report on experiences with the implementation and use of the system.

A weight-of-evidence approach to assess chemicals: case study on the assessment of persistence of 4,6-substituted phenolic benzotriazoles in the environment.

BACKGROUND: One important purpose of the European REACH Regulation (EC No. 1907/2006) is to promote the use of alternative methods for assessment of hazards of substances in order to avoid animal testing. Experience with environmental hazard assessment under REACH shows that efficient alternative methods are needed in order to assess chemicals when standard test data are missing. One such assessment method is the weight-of-evidence (WoE) approach. In this study, the WoE approach was used to assess the persistence of certain phenolic benzotriazoles, a group of substances including also such of very high concern (SVHC). RESULTS: For phenolic benzotriazoles, assessment of the environmental persistence is challenging as standard information, i.e. simulation tests on biodegradation are not available. Thus, the WoE approach was used: overall information resulting from many sources was considered, and individual uncertainties of each source analysed separately. In a second step, all information was aggregated giving an overall picture of persistence to assess the degradability of the phenolic benzotriazoles under consideration although the reliability of individual sources was incomplete. CONCLUSIONS: Overall, the evidence suggesting that phenolic benzotriazoles are very persistent in the environment is unambiguous. This was demonstrated by a WoE approach considering the prerequisites of REACH by combining several limited information sources. The combination enabled a clear overall assessment which can be reliably used for SVHC identification. Finally, it is recommended to include WoE approaches as an important tool in future environmental risk assessments.

A new integrated in silico strategy for the assessment and prioritization of persistence of chemicals under REACH.

The fact that chemicals can be recalcitrant and persist in the environment arouses concern since their effects may seriously harm human and environmental health.We compiled three datasets containing half-life (HL) data on sediment, soil and water compartments in order to build in silico models and, finally, an integrated strategy for predicting persistence to be used within the EU legislation Registration, Evaluation, Authorisation and restriction of CHemicals (REACH). After splitting the datasets into training (80%) and test sets (20%), we developed models for each compartment using the k-nearest neighbor algorithm (k-NN). Accuracy was higher than 0.79 and 0.76 respectively in the training and test sets for all three compartments. To support the k-NN predictions, we identified some structural alerts, using SARpy software, with a high-true positive percentage in the test set and some chemical classes related to persistence using the software IstChemFeat. All these results were combined to build an integratedmodel and to reach to an overall conclusion (based on assessment and reliability) on the persistenceof the substance. The results on the external validation set were very encouraging and support the idea that this tool can be used successfully for regulatory purposes and to prioritize substances.

Semipolar polycyclic aromatic compounds: identification of 15 priority substances and the need for regulatory steps under REACH regulation.

Semipolar polycyclic aromatic compounds (sPACs) are frequently found in association with homocyclic polycyclic aromatic hydrocarbons (PAHs) in substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs) from coal or crude oil and products derived thereof. However, major information deficiencies exist with regard to their prevalence and their toxicological and ecotoxicological potential, persistency, and bioaccumulation characteristics. Therefore, in this work, the environmental concern and relevance of sPACs was addressed in a general, stepwise approach. First, a large list of sPACs was collected and subsequently refined by assessing their persistence, bioaccumulation, and toxicity (PBT) properties by quantitative structure-activity relationship (QSAR) methods and their relevance by determining their respective frequency of occurrence. In this way, 15 priority sPACs were identified. These 15 priority sPACs were further characterized in detail with respect to their ecotoxicological properties, environmental behavior, carcinogenicity, and genotoxicity attributes. All of these 15 substances were quantified in distillate or product samples. In the next step, some principles for nomination of indicator substances, indicative for the overall content of sPACs, are derived. Data gaps on ecotoxicological endpoints preclude final conclusions, but the respective necessary supplemental tests were identified. Five of the 15 sPACs were tentatively characterized as potential substances of very high concern (SVHC) for the environment. The overall results of this study also clearly show that regulatory risk management of homocyclic PAHs within the European Regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) does not address the environmental concern created by sPACs within UVCBs from coal or crude oil. The study proves the need for additional regulatory steps under REACH and suggests indicator substances for their enforcement.