10th German Pharm-Tox Summit / 91. Jahrestagung der Deutschen Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (DGPT)

Considerations and challenges for Acute Inhalation Toxicity Testing and Classification of Zinc sulphide under REACH

Inhalation Toxicology

TOX02

Zinc sulphide is a widely used inorganic powder, and its production has reached quantities greater than 1000 t/year. Previous assessments using a read-across approach with other inorganic zinc substances have proven unreliable for predicting toxicity. Therefore, in accordance with OECD guideline 436, an acute inhalation test was implemented to provide more accurate data. This study is crucial for ensuring the safety of workers exposed to zinc sulphide dust and complying with regulatory requirements for occupational health.Due to particle specific properties the maximum attainable concentration of zinc sulphide for an inhalation study was not certain. Two dry dispersion systems were used to aerosolize the zinc sulphide powder, and the generated aerosol was supplied to a nose-only inhalation exposure system. The chamber concentration was measured using an aerosol photometer and a glass fiber filter. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the aerosol were also measured using a cascade impactor. The results showed a maximum attainable chamber concentration of 0.82 mg/L at an MMAD of 1.5 µm consistent over a 4-hour exposure period. The test evaluated respiratory tract effects in rats, as the preferred species following OECD 436. In the study all 6 rats showed no specific symptoms, a good general health status and survived post-exposure observation period up to 14 days. From the results observed the status Unclassified was derived according to GHS. Based on the experimental results, an LC50 was not determined but is considered higher than 0.82 mg/L (the maximum achievable concentration).

Toxicology

Poster Self-Study

Prof. Dr.

Prof. Dr. DR.

MAK value for glass wool with low biopersistency – no carcinogenic effect at low concentrations

The Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) proposes maximum workplace concentrations (MAK values) for chemicals in order to provide comprehensive information to occupational safety professionals and researchers and to give scientific policy advice.In humans, the target organs after inhalation of fibres are the lungs, larynx and pleura. A long half-life and repeated absorption of fibres can lead to inflammatory reactions, fibrosis and tumours in these tissues/organs.For fibres with a half-life of less than 40 days after intratracheal administration in rats, no carcinogenic potential is expected. In the case of glass wool of low biospersistency (half-life < 40 days), an occupational exposure limit value has been set by the Commission that protects from fibre toxicity. As no inhalation studies are available for these glass wools, the results of inhalation studies with the more persistent glass wools MMVF10 and MMVF11 are used. In rats low irritative effects in the lung occurred in 2-year inhalation study at 3,1 mg/m3.The MAK value was calculated using two approachs: Taking into account differences between rats and humans by assessment factors a MAK value of 0.1 mg/m3 for the respirable fraction of glass wool (fibrous and granular components) with a half-life of less than 40 days (after intratracheal administration of WHO fibres) can be derived from these studies. A second method calculated the human equivalent concentration with the deposition fractions of the fibres, which are determined using the MPPD model. Taking into account differences between rats and humans in life-time exposure, respiratory volume, lung surface and deposition fraction, the averaged calculated value confirmed the MAK value of 0.1 mg/m3 for the respirable fraction.

Translational testing of inhaled nanoparticles

Background and Purpose:The recent SARS-CoV-2 pandemic revealed a long-time underestimated demand for rapidly available substances to treat infections of novel pathogens. Subsequently, newly developed inhaled therapeutics can prevent and combat viral infections. As many viruses enter the body through the nasal cavity and the deeper respiratory tract, nanoparticle-based drugs can be adapted for inhalation to enable drug activity directly at the site of infection. As inhalable drugs, nanoparticles, such as lipid, coated, or encapsulated nanoparticles, need precise pre-clinical toxicity testing as a requirement for translation into clinical phase I testing.Methods:For preclinical toxicity testing of inhalable drug candidates, we developed a tiered approach in which aerosols can be tested for efficacy and acute inhalation toxicity in ex vivo models such as the isolated perfused lung (IPL). The IPL model provides a fully intact organ system with cellular, structural, and functional integrity, including pulmonary barrier function and circulation, which are exposed to aerosols in a dose escalation scheme. In the next step, the inhalable nanoparticles can be tested in a subacute dose-range finding study (DRF), guiding the required GLP-toxicity study in small and large animal models to transfer the candidate to the clinical phase I stage.Results:The Fraunhofer ITEM transferred several inhaled nanoparticles from the pre-clinical to the clinical stage, highlighting at least two facts. On the one hand, this demonstrates the huge potential of inhalation as a new, sufficient, and safe application route, being successful where other routes fail. On the other hand, this also underlines the importance of inhalation in developing new treatments for emerging pathogens.

Poster Walk 3
Inhalation Toxicology

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Programm

Poster Walk 3Inhalation Toxicology

Termin

Programm

Poster Walk 3
Inhalation Toxicology