Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
According to column 2 of Annex IX "Testing by the inhalation route is appropriate if: — exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size."
Toxic effects in humans by inhalation of the substance are unlikely, not only by the intended uses, but also because the substance has a very low vapour pressure. The substance is used as an intermediate in a closed process in industrial sites, with no likelihood of exposure. No professional or consumer exposure is intended.
An acute inhalation toxicity study in rats did not show systemic toxic effects at the highest limit concentration of 5 mg/L, therefore not indicating systemic effects after inhalation exposure.
Also local effects of mucous membranes are not likely. An indication was obtained from the in vitro eye irritation studies showing no irritation of the mucuous membrane. In the acute inhalation toxicity test, only dyspnoe during and shortly after the exposure period (which is likely a sign of discomfort of the rats being restricted in the inhalation tubes, because the same signs were reported in the last 8 reports of this specific test facility applying quite different substances), and no macroscopic lesions were observed with aerosols of the test item. Therefore no relevant indications were obtained that the test item might cause local lesions to the mucosa of the respiratory tract.
The NOEC for the inhalation route can be derived from the NOELoral, taking into account a higher (2-fold) absorption at inhalation compared to oral, as is described in the Guidance Document on Information Requirements Chapter R.8.4.2. It is considered that this approach is sufficient for a risk assessment.
The oral toxicity studies are performed more routinely than the inhalation experiments, and they cause less complications and more reliable results. In the ECHA Guidance on Info Requirements Part 7.a of August 2014, p. 294 it is stated "Concerning repeated dose toxicity testing the oral route is the preferred one. However, ...".
The revised guideline of July 2017 states: "Concerning repeated dose toxicity testing, the oral route is the default one because it is assumed to maximise systemic availability (internal dose) of most substances."And also: "Testing by the inhalation route is the default route for gases and the preferred route for liquids of high to very high vapour pressure at ambient temperature (>25 kPa or boiling point below 50 °C) for which inhalation is usually the predominant route of human exposure." And: "... for dusts (including nanomaterials), testing by the inhalation route is appropriate if human inhalation exposure is likely ...". The test substance is not a liquid, it has a low vapour pressure and the exposure of humans is unlikely.

The NOEC for the inhalation route can be derived from the NOELoral, taking into account a higher (2-fold) absorption at inhalation compared to oral, as is described in the Guidance Document on Information Requirements Chapter R.8.4.2. It is considered that this approach is sufficient for a risk assessment.

An inhalation animal experiment is therefore considered not to be justified.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion