Regenerative and progressing lesions in lungs and lung-associated lymph nodes from fourteen 90-day inhalation studies...

Rat lungs and lung-associated lymph nodes from 14 inhalation studies with chemically different particulate materials were histopathologically re-evaluated, and the bronchoalveolar lavage fluid (BALF) data and lung burden analyses were compared. All investigated substances caused similar lesions. For most substances, 1 mg/m³ of respirable particulate matter was established as the borderline for adverse morphological changes after the 90-day exposure period, confirmed by the increase in polymorphonuclear neutrophils in BALF. Possible reversibility was demonstrated when recovery groups are included in the study especially allowing the differentiation between regeneration or progressing of inflammatory changes during the recovery period. It was concluded, that the major driver of toxicity is not an intrinsic chemical property of the particle but a particle effect. Concerning classification for specific target organ toxicant (STOT) repeated exposure (RE), this paper highlights that merely comparing the lowest concentration, at which adverse effects were observed, with the Classification Labelling and Packaging (CLP) regulation (EC) no. 1272/2008 guidance values is inappropriate and might lead to a STOT classification under CLP for a large part of the substances discussed in this paper, on the basis of typically mild to moderate findings in rat lung and lung-associated lymph nodes on day 1 after exposure. An in-depth evaluation of the pathologic findings is required and an expert judgement has to be included in the decision on classification and labeling, evaluating the type and severity of effects and comparing these with the classification criteria.