The Grouping and Assessment Strategy for Organic Pigments (GRAPE): Scientific evidence to facilitate regulatory decision-making

• Published in: Regulatory toxicology and pharmacology 2019-12, Vol.109, p.104501, Article 104501
• Main Authors: Sauer, Ursula G., Kreiling, Reinhard
• Format: Article
• Language: English
• Subjects: (bio)dissolution; 3Rs principle (replace; Alveolar macrophages; Animal Use Alternatives - legislation & jurisprudence; Bioavailability; Biological Availability; Caco-2 cell line; Caco-2 Cells; Cell Membrane Permeability; Coloring Agents - chemistry; Coloring Agents - pharmacokinetics; Coloring Agents - toxicity; Decision Making; EU REACH regulation; European Union; Human health protection; Humans; Inhalation exposure; Inhalation Exposure - adverse effects; Oral exposure; Quantitative Structure-Activity Relationship; Reduce; Refine animal testing; Regulatory toxicology; Solubility; Toxicity Tests - standards
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2019.104501

This article presents the Grouping and Assessment Strategy for Organic Pigments (GRAPE). GRAPE is driven by the hypotheses that low (bio)dissolution and low permeability indicate absence of systemic bioavailability and hence no systemic toxicity potential upon oral exposure, and, for inhalation exposure, that low (bio)dissolution (and absence of surface reactivity, dispersibility and in vitro effects) indicate that the organic pigment is a ‘poorly soluble particle without intrinsic toxicity potential’. In GRAPE Tier 1, (bio)solubility and (bio)dissolution are assessed, and in Tier 2, in vitro Caco-2 permeability and in vitro alveolar macrophage activation. Thereafter, organic pigments are grouped by common properties (further considering structural similarity depending on the regulatory requirements). In Tier 3, absence of systemic bioavailability is verified by limited in vivo screening (rat 28-day oral and 5-day inhalation toxicity studies). If Tier 3 confirms no (or only very low) systemic bioavailability, all higher-tier endpoint-specific animal testing is scientifically not-relevant. Application of the GRAPE can serve to reduce animal testing needs for all but few representative organic pigments within a group. GRAPE stands in line with the EU REACH Regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals). An ongoing research project aims at establishing a proof-of-concept of the GRAPE. •The Grouping and Assessment Strategy for Organic Pigments (GRAPE) is presented.•Low (bio)dissolution & low in vitro permeability indicate no oral bioavailability.•Low (bio)dissolution & specific further parameters: no inhalation bioavailability.•Prediction of no systemic bioavailability indicates absence of toxicity potential.•GRAPE serves to reduce regulatory animal testing to the absolute minimum.