Data from a repeated dosing sub-acute,

sub-chronic or chronic inhalation study are ideal. If data are limited, extrapolation from studies on a structurally related and biologically inert chemical may be useful. On the basis of such data a safe air concentration based on LDE225 in vivo experimental data may be estimated. Other ingredients in cosmetic sprays are usually present at low levels so that exposure is likely to be low. Analogous to the approaches described above, all ingredients need to be evaluated. Particular attention should be given to potential human inhalation exposure to fine droplets of lipophilic/oily substances, since such formulations may produce the so-called “acute respiratory syndrome” in exposed humans (Vernez et al., 2006). Mucosal irritation can be caused by reactive chemical species. Water-soluble and hydrophilic compounds tend to remain in the mucosa of the upper airways, while more lipophilic and less water-soluble substances may penetrate deeper into the lung. Two types of irritation can be distinguished: a) irritation of nerve endings in the upper respiratory tract without adverse changes in pulmonary tissue (sensory irritation) or b) local toxic effects producing local adverse changes in pulmonary tissue(s). The irritation potential of a given chemical may be evaluated based on standardised inhalation toxicity studies in rodents or by employing mathematical

models which Montelukast Sodium take into consideration known data on lung irritants. Also in vitro eye or skin irritation tests may

be helpful to evaluate a potential sensory PI3K inhibitor irritation of the ingredient (Weight-of Evidence Approach). In the EU, known respiratory irritants are labelled with the hazard statement H335 (former risk phrase R37); irritates respiratory organs/respiratory irritant (EU Regulation 1272/2008, European Parliament and Council, 2008; former Council Directive 67/548/EEC). The majority of these chemicals are listed in ChemDat (Merck Chemie Datenbank, Editor: Merck KGaA, 64271 Darmstadt, 2000) and in TRGS 900 (BAuA, 2006) and carry at least one other warning label regarding irritation hazard effects on eyes, skin, etc. (H314, H319, H318, H315; former R34, R35, R36, R41, R38). However, one may assume that most substances which are irritant to the skin or eyes may also possess a potential being a respiratory irritant. The new EU Regulation 1272/2008 (Regulation on classification, labelling and packaging “CLP Regulation” which is currently implemented stepwise and which uses a different nomenclature for risk phrases has to be considered in future. This Regulation is in line with the UN Globally Harmonized System of Classification and Labelling of Chemicals (quoted in the EU Regulation 1272/2008). Due to the huge surface area of the lung significant systemic absorption of ingredients are likely, especially when they reach the alveoli.