Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
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 dermal route is appropriate if:
(1) skin contact in production and/or use is likely; and
(2) the physicochemical properties suggest a significant rate of absorption through the skin; and
(3) one of the following conditions is met:
— toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or
— systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, or
— in vitro tests indicate significant dermal absorption, or
— significant dermal toxicity or dermal penetration is recognised for structurally-related substances."

Testing by the dermal route is not appropriate because:
• The skin contact in production and/or use is not likely. The substance is only used as an intermediate in industry in closed processes. There are no professional or consumer uses.
• The physicochemical and toxicological properties do not suggest a potential for a significant rate of absorption through the skin that is higher than the absorption at oral exposure.
Based on the Section R.7.12.2.1 of the 'Guidance on information requirements and chemical safety assessment' an even lesser dermal absorption, compared to the oral absorption, is predicted, because the n-octanol/water partition coefficient of the test item is lower than -3.4. For substances with log P values <0, the poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. log Pow <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low. The substance must also be sufficiently soluble in water to partition from the stratum corneum into the epidermis. The medium water solubility of the test item of 0.61 g/L will enable only a low to moderate dermal absorption.
• None of the 4 conditions listed in paragraph (3) of column 2 are met.
Conclusion: None of the criteria in paragraphs (1), (2) and (3) of column 2 of Annex IX are fulfilled, therefore it is not appropriate to propose the dermal route for the repeated dose toxicity study.

Additional arguments contra a dermal toxicity study are:
• It is generally accepted that the dermal absorption is usually lower than the oral one, leading to a lower toxicity after dermal exposure than after the oral one.
• Also local effects are not expected for the substance as no skin irritation was observed in an in vivo study.
• The oral toxicity studies are performed more routinely than the dermal or 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."
• A risk assessment do not need the results from a dermal toxicity study but can be performed with a study with oral dosing.

Conclusion: No new and relevant information are expected from a dermal repeated dose toxicity study compared to the otherwise similar oral study.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion