PBT/PMT assessment of active pharmaceutical ingredients.

The EU Commission proposal for a new EU pharmaceutical legislation considers PBT (persistence-bioaccumulation-toxicity) and PMT (persistence-mobility-toxicity) criteria for pharmaceuticals. Under current environmental risk assessment guidance, a PBT assessment is required regardless of the predicted environmental concentrations. However, consumption volumes of pharmaceuticals are contingent on marketing approval by EMA and are therefore predictable and their toxicological potency is established prior to any regulatory approval.

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control.

Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients.

Developing Integrated Approaches for Testing and Assessment (IATAs) in order to support nanomaterial safety.

Due to the unique characteristics of nanomaterials (NM) there has been an increase in their use in nanomedicines and innovative medical devices (MD). Although large numbers of NMs have now been developed, comprehensive safety investigations are still lacking. Current gaps in understanding the potential mechanisms of NM-induced toxicity can make it challenging to determine the safety testing necessary to support inclusion of NMs in MD applications.

Integrated approaches to testing and assessment for grouping nanomaterials following dermal exposure.

Exposure to different nanoforms (NFs) the dermal route is expected in occupational and consumer settings and thus it is important to assess their dermal toxicity and the contribution of dermal exposure to systemic bioavailability. We have formulated four grouping hypotheses for dermal toxicity endpoints which allow NFs to be grouped to streamline and facilitate risk assessment. The grouping hypotheses are developed based on insight into how physicochemical properties of NFs (i.

Possibilities to group nanomaterials across different substances - A case study on organic pigments.

Grouping concepts to reduce the testing of NFs have been developed for regulatory purposes for different forms of the same substance. Here we explore possibilities to group nanomaterials across different substances for non-regulatory applications, using the example of 16 organic pigments from six chemical classes. Organic pigments are particles consisting of low-molar-mass organic molecules, and rank by tonnage among the most important substances manufactured in nanoform (NF).

Towards health-based nano reference values (HNRVs) for occupational exposure: Recommendations from an expert panel.

Unique physicochemical characteristics of engineered nanomaterials (ENMs) suggest the need for nanomaterial-specific occupational exposure limits (OELs). Setting these limits remains a challenge. Therefore, the aim of this study was to set out a framework to evaluate the feasibility of deriving advisory health-based occupational limit values for groups of ENMs, based on scientific knowledge.

An integrated approach to testing and assessment of high aspect ratio nanomaterials and its application for grouping based on a common mesothelioma hazard.

Here we describe the development of an Integrated Approach to Testing and Assessment (IATA) to support the grouping of different types (nanoforms; NFs) of High Aspect Ratio Nanomaterials (HARNs), based on their potential to cause mesothelioma. Hazards posed by the inhalation of HARNs are of particular concern as they exhibit physical characteristics similar to pathogenic asbestos fibres. The approach for grouping HARNs presented here is part of a framework to provide guidance and tools to group similar NFs and aims to reduce the need to assess toxicity on a case-by-case basis.

How can we justify grouping of nanoforms for hazard assessment? Concepts and tools to quantify similarity.

The risk of each nanoform (NF) of the same substance cannot be assumed to be the same, as they may vary in their physicochemical characteristics, exposure and hazard. However, neither can we justify a need for more animal testing and resources to test every NF individually. To reduce the need to test all NFs, (regulatory) information requirements may be fulfilled by grouping approaches.

Grouping Hypotheses and an Integrated Approach to Testing and Assessment of Nanomaterials Following Oral Ingestion.

The risk assessment of ingested nanomaterials (NMs) is an important issue. Here we present nine integrated approaches to testing and assessment (IATAs) to group ingested NMs following predefined hypotheses. The IATAs are structured as decision trees and tiered testing strategies for each decision node to support a grouping decision.

Creating sets of similar nanoforms with the ECETOC NanoApp: real-life case studies.

The ECETOC NanoApp was developed to support industry in the registration of sets of nanoforms, as well as regulators in the evaluation of these registration dossiers. The ECETOC NanoApp uses a systematic approach to create and justify sets of similar nanoforms, following the ECHA guidance in a transparent and evidence-based manner. The rational and decision rules behind the ECETOC NanoApp are described in detail in "Janer, G.

Rationale and decision rules behind the ECETOC NanoApp to support registration of sets of similar nanoforms within REACH.

New registration requirements for nanomaterials under REACH consider the possibility to form 'sets of similar nanoforms' for a joined human health and environmental hazard, exposure and risk assessment. We developed a tool to create and justify sets of similar nanoforms and to ensure that each of the nanoforms is sufficiently similar to all other nanoforms. The decision logic is following the ECHA guidance in a transparent and evidence-based manner.

A review to support the derivation of a worst-case dermal penetration value for nanoparticles.

Data on dermal penetration of nanoparticles (NPs) was reviewed with the goal to establish a worst-case dermal penetration value for NPs. To this aim, the main focus was on studies providing quantitative dermal penetration data (29 studies). In vivo dermal penetration studies and ex vivo studies based on skin explants were included.

Short-term oral administration of non-porous and mesoporous silica did not induce local or systemic toxicity in mice.

In this study, two sets of methyl-coated non-porous and mesoporous amorphous silica materials of two target sizes (100 and 300 nm; 10-844 m/g) were used to investigate the potential role of specific surface area (SSA) and porosity on the oral toxicity in mice. Female Swiss mice were administered by oral gavage for 5 consecutive days. Two silica dose levels (100 and 1000 mg/kg b.

Physiologically based mathematical models of nanomaterials for regulatory toxicology: A review.

The development of physiologically based (PB) models to support safety assessments in the field of nanotechnology has grown steadily during the last decade. This review reports on the availability of PB models for toxicokinetic (TK) and toxicodynamic (TD) processes, including and dosimetry models applied to manufactured nanomaterials (MNs). In addition to reporting on the state-of-the-art in the scientific literature concerning the availability of physiologically based kinetic (PBK) models, we evaluate their relevance for regulatory applications, mainly considering the EU REACH regulation.

In vitro assessment of CeO nanoparticles effects on intestinal microvilli morphology.

Some nanoparticles (NPs) have been shown to disrupt intestinal microvilli morphology in vitro, an alteration that could potentially affect nutrient absorption and barrier properties. This study aimed at evaluating the potential effect of CeO NPs (4-8 nm, citrate stabilized) on Caco-2 microvilli morphology. In addition to the standard Caco-2 cell clone, the C2BBe1 clone was used, as it is considered to develop a more homogeneous cellular morphology.

Development of a systematic method to assess similarity between nanomaterials for human hazard evaluation purposes - lessons learnt.

Within the EU FP-7 GUIDEnano project, a methodology was developed to systematically quantify the similarity between a nanomaterial (NM) that has been tested in toxicity studies and the NM for which risk needs to be evaluated, for the purpose of extrapolating toxicity data between the two materials. The methodology is a first attempt to use current knowledge on NM property-hazard relationships to develop a series of pragmatic and systematic rules for assessing NM similarity. Moreover, the methodology takes into account the practical feasibility, in that it is based on generally available NM characterization information.

Acute ecotoxicity of coated colloidal goethite nanoparticles on Daphnia magna: Evaluating the influence of exposure approaches.

Synthesized iron oxide nanoparticles have been proposed as an alternative to non-dispersed iron oxides for in situ environmental remediation. Their colloidal properties enable their injection into porous media, i.e.

The Life Cycle of Engineered Nanoparticles.

The first years in the twenty-first century have meant the inclusion of nanotechnology in most industrial sectors, from very specific sensors to construction materials. The increasing use of nanomaterials in consumer products has raised concerns about their potential risks for workers, consumers and the environment. In a comprehensive risk assessment or life cycle assessment, a life cycle schema is the starting point necessary to build up the exposure scenarios and study the processes and mechanisms driving to safety concerns.

Towards a nanospecific approach for risk assessment.

In the current paper, a new strategy for risk assessment of nanomaterials is described, which builds upon previous project outcomes and is developed within the FP7 NANoREG project. NANoREG has the aim to develop, for the long term, new testing strategies adapted to a high number of nanomaterials where many factors can affect their environmental and health impact. In the proposed risk assessment strategy, approaches for (Quantitative) Structure Activity Relationships ((Q)SARs), grouping and read-across are integrated and expanded to guide the user how to prioritise those nanomaterial applications that may lead to high risks for human health.

Influence of Nanomaterial Compatibilization Strategies on Polyamide Nanocomposites Properties and Nanomaterial Release during the Use Phase.

The incorporation of small amounts of nanofillers in polymeric matrices has enabled new applications in several industrial sectors. The nanofiller dispersion can be improved by modifying the nanomaterial (NM) surface or predispersing the NMs to enhance compatibility. This study evaluates the effect of these compatibilization strategies on migration/release of the nanofiller and transformation of polyamide-6 (PA6), a thermoplastic polymer widely used in industry during simulated outdoors use.

Engineered Nanoscale Food Ingredients: Evaluation of Current Knowledge on Material Characteristics Relevant to Uptake from the Gastrointestinal Tract.

The NanoRelease Food Additive project developed a catalog to identify potential engineered nanomaterials (ENMs) used as ingredients, using various food-related databases. To avoid ongoing debate on defining the term nanomaterial, NanoRelease did not use any specific definition other than the ingredient is not naturally part of the food chain, and its dimensions are measured in the nanoscale. Potential nanomaterials were categorized based on physical similarity; analysis indicated that the range of ENMs declared as being in the food chain was limited.

Cell uptake and oral absorption of titanium dioxide nanoparticles.

Large efforts are invested on the development of in vitro tests to evaluate nanomaterial (NM) toxicity. In order to assess the relevance of the adverse effects identified in in vitro toxicity tests a thorough understanding of the biokinetics of NMs is critical. We used different in vitro and in vivo test methods to evaluate cell uptake and oral absorption of titanium dioxide nanoparticles (TiO2 NPs).

In vitro toxicity of functionalised nanoclays is mainly driven by the presence of organic modifiers.

Little information exists on the toxicological hazards associated to organo-modified clays. We evaluated the cytotoxicity of a series of pristine and organo-modified nanoclays in different cell lines. The calculated IC50 values for cell viability ranged from 1.

The intestinal anti-inflammatory effect of dersalazine sodium is related to a down-regulation in IL-17 production in experimental models of rodent colitis.

Background And Purpose: Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR-12715) with 5-aminosalicylic acid (5-ASA). DS has been demonstrated to have anti-inflammatory effects on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD).