Investigation on the skin penetration of synthetic amorphous silica (SAS) used in cosmetic products.

Synthetic amorphous silica (SAS) is used as additive in a variety of industrial applications for many decades and has been approved to be used in food, food contact materials, pharmaceuticals, and cosmetics. Due its internal structure, SAS is considered as a nanomaterial, thus it is affected by a general safety discussion. Based on the production process, SAS for cosmetic application is a nanomaterial by the EU Recommendation, although it was not considered as such, because the solely size-dependent definitions of the term "nanomaterial" emerged in recent times first in Recommendation 2011/696/EU. Therefore, former physicochemical and toxicological evaluations of SAS were already performed on nanomaterials, however, without being addressed as such. Safety concerns can only emerge if two criteria, (toxicological) hazard and exposure towards the substance is fulfilled at the same time. In case of SAS, the Scientific Committee on Consumer Safety (SCCS) challenged provided data to be insufficient to draw a conclusion regarding the safety of SAS and thus, requested further investigations, in particular by exploring skin penetration of particulate SAS.Investigation of specific particulate substances in skin penetration tests is an analytical challenge. The number of available analytical techniques that are capable to detect nanomaterials in complex matrices, like receptor fluids from skin penetration testing, are limited and still emerging. In the new studies, a comprehensive set of analytical techniques were used to investigate the skin penetration potential of SAS. Particle-sensitive, element and particle-specific combinations of techniques and different sample preparation procedures, that respected the particulate nature of SAS, were used to detect SAS in receptor fluids directly. In addition, electron microscopic techniques were used to examine different layers of skin to detect adsorbed SAS.The combination of Asymmetric Flow Field-Flow Fractionation (AF4) in combination with Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for examination of receptor fluids and Scanning Electron Microscopy coupled with Energy Dispersive X-ray spectroscopy (SEM/EDX) for examination of skin itself, were identified as suitable techniques for the detection of SAS in skin penetration tests. Data from literature was used to compare the results of the studies with the outcome of other test systems (other particles, other techniques). Both, the test results, and literature evaluation led to the conclusion, that SAS does not penetrate skin. Based on this outcome and local and systemic dermal toxicity review of SAS, it can be concluded that dermal application of SAS in cosmetic formulations is negligible.

Issues in the inhalation toxicity testing and hazard assessment for low density particulate materials such as synthetic amorphous silica (SAS).

Inhalation toxicity testing of particulate materials is mandated for classification. According to CLP, particulate materials should be tested as marketed and many particulate materials are marketed as non-respirable particles. However, OECD TG 413 requires exposure to particle sizes that are respirable and reach the alveoli. The requirement for exposure of rats to respirable particles is thus in contrast to CLP and requires the application of high shear forces. The exposure to artificially small particles causes a number of issues that hamper the interpretation of the results of the testing. These issues are aerosol altering in the exposure system, assessment of the adversity of the inflammatory lung responses, inclusion of recovery groups, and extrapolation of the results to humans exposed under occupational condition. In addition, effects of many particulate materials after testing according to OECD 413 are not intrinsic properties, but a general reaction of the lung to the deposited material, show very similar NOAECs for chemical diverse materials, and often are completely reversible.

Assessment of the skin sensitisation hazard of functional polysiloxanes and silanes in the SENS-IS assay.

In the context of a larger testing programme that aimed at assessing the skin sensitisation potential of functional polysiloxanes and silanes, this investigation complements the available in vitro and in vivo data with data in the SENS-IS assay, a human in vitro 3D skin-based model. The SENS-IS assay allowed testing of all functional polysiloxanes and silanes without any solubility issues or limitations related to the multiconstituent nature of the commercial grade test substances. It appeared to encompass skin metabolism, a factor which we considered important for the skin sensitisation hazard assessment particularly of aminofunctionalised siloxanes and silanes. These three technical aspects posed significant challenges in the first part of the in vitro programme with the OECD-validated in vitro assays. The SENS-IS assay delivered promising results for this group of substances. On its own, it was the best performing model, as it did not pose any technical issues with the assay and it matched all in vivo outcomes. Considering its performance and avoidance of any limitations due to lack of solubility or chemical composition aspects, we concluded that the SENS-IS assay to be a suitable starting point for an integrated testing strategy for skin sensitisation for the group of functional polysiloxanes and silanes.

Evaluation of in vitro assays for the assessment of the skin sensitization hazard of functional polysiloxanes and silanes.

The skin sensitization potential of chemicals has traditionally been evaluated in vivo according to OECD testing guidelines in guinea pigs or the mouse local lymph node assay. There has lately been a great emphasis on establishing in vitro test methods reflecting the key biological events in the adverse outcome pathway (AOP) for skin sensitization as published by the OECD. Against this background, a group of 8 polysiloxanes and silanes, seven of them aminofunctionalised, for which in vivo data were already available, has been tested in vitro in the direct peptide reactivity assay (DPRA), the KeratinoSens™ and the human cell line activation test (h-CLAT) and in the modified myeloid U937 skin sensitization test (mMUSST) as far as technically feasible. The main objective of the programme was to determine the utility of these systems for this heterogeneous group of silicone-based substances, recognizing that some substances are outside the assays applicability domains. The presented data provided some interesting mechanistical insights into the performance of these assays for functionalised siloxanes and silanes. The data also allow for a preliminary evaluation of proposed integrated testing strategies (ITS) to determine the skin sensitization potential of chemicals which were not considered in the training sets of the respective ITS.

Cross-sectional study on respiratory morbidity in workers after exposure to synthetic amorphous silica at five German production plants: exposure assessment and exposure estimates.

OBJECTIVES: Synthetic amorphous silicas (SASs) are nanostructured polymorphs of silicon dioxide. We compared two different exposure assessments. METHODS: This study estimated cumulative exposure to inhalable SAS dust in 484 male workers from five German SAS-producing plants. Two procedures (P1 and P2) were applied. P1 was based on an expert assessment. P2 was a multiple exposure assessment (15 scenarios) anchored by a recent measurement series (1375 personal measurements of inhalable SAS dust concentration) and used expert assessments. RESULTS: Cumulative exposure estimates for P1 averaged 56.9 mg/m·yrs (range, 0.1 to 419); for a selected P2 scenario, the mean was 31.8 mg/m·yrs (range, 0.4 to 480), (P < 0.0001). Averages varied between the 15 P2-scenarios from 12.6 to 109.6 mg/m·yrs. Different time trends for SAS concentrations were observed. CONCLUSIONS: Both approaches suffer from considerable uncertainties that need to be considered in epidemiological studies.

An assessment of the skin sensitisation hazard of a group of polyfunctional silicones using a weight of evidence approach.

Discordant results were observed when testing five prototype polyfunctional silicone materials for skin sensitization potential in the murine local lymph node assay (LLNA) and in the guinea pig maximization test (GPMT). While all five silicone materials were consistently negative in the GPMT, the testing in the LLNA revealed weak to moderate skin sensitisation potential for four of the five test materials. Neither study quality nor other known chemical factors could explain these findings. Further analysis did not provide sufficient evidence for a link between the LLNA responses and the irritancy of the test substances. Only in the case of one of the test materials, the occurrence of an excessive level of irritation could be linked to the positive LLNA result. Considering all existing information including physico-chemical and structure activity and animal data as well as existing human experience from silicone exposures at the workplace or their use in cosmetic products, the weight of evidence suggests that none of the examined silicone materials represents a significant skin sensitization hazard to humans. The suitability of the LLNA appears questionable for this class of materials. In case of any additional data needs for other or new silicone materials, the skin sensitization testing strategy will require careful evaluation and will need to be set up on a case by case basis.