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Description of key information

There is a GLP in vitro dermal absorption study performed according to OECD 428. No other information is available on in vivo metabolism.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
0.01

Additional information

There is no in vivo toxicokinetic study performed with AZDN and no study available on the metabolism of the substance in vivo.

In vitro, a dermal penetration study was performed on human skin according to OECD 428 (Jaguer, 2011).

In this study, the test item AZDN was assessed for its potential to permeate human skin. AZDN was the measured compound. For the test item 12 replicates were analysed. 5 mg of the test item were applied to each chamber for 24 hours and then removed by washing each skin sample nine times with 1 mL extraction solution. PBS was used as the receptor fluid. The conductivity across the skin samples of each chamber was measured before treatment and after the sampling. No abrupt change in conductivity, indicating a loss of barrier properties of the skin, occurred in any chamber up to the maximal duration of the experiment, except for chamber 3 in experiment 1, where removal of the upper part of the skin could be observed after the experiment. The samples were analysed by LC-MS/MS for the presence of AZDN. For the test item two experiments with 6 replicates each were performed under non- occluded conditions. Two chambers did not meet the acceptance criteria (chamber 3 in experiment 1; chamber 4 in experiment 2) and, therefore, 10 chambers were used for the analysis of AZDN. In total 4 donors were used in this study. In conclusion, it can be stated that during the described permeability test and under the experimental conditions reported, AZDN showed penetration into the viable skin layers and the receptor fluid out of the test item dilution with 0.480 +/- 0.220 µg/cm2 (0.010 +/-0.005 % of applied dose).

The mean penetrated amount is 480 ng/cm² +/- 220 ng/cm² or 0.0103% +/-0.0052% of applied dose.

Physicochemical Properties of AZDN Relevant to Toxicokinetics

Molecular weight: 164 g/mol

Water solubility: Appreciably soluble (317 mg/L)

n-Octanol/water partition coefficient (Log Pow): 1.10 at 25°C

Vapour pressure: 0.81 Pa at 25°C

Toxicokinetic Assessment:

Considering the physicochemical properties of AZDN, [i.e.,low molecular weight (167 g/mol) and log Pow value < 1.10 and the high solubility, absorption of AZDN from various routes of exposure, such as oral, dermal or inhalation is expected. This is confirmed in the in vitro dermal penetration study (Jaguer, 2011) where low absorption was measured through Human skin. Furthermore as AZDN is a solid with a mean granulometry diameter around 98µm, inhalation of particles are considered of low potential despite the classification as harmful by inhalation by the EU regulation 1272/2008.

The results for the acute oral studies and the repeated toxicity studies also indicated some absorption via oral route : In the acute oral toxicity study, the presence of systemic effects such as hypoactivity, piloerection and rhinorrhea in all the animals on days 1 and/or 2 at 300 mg/kg/day and at 2000 mg/kg (three females) of Hypoactivity then sedation, piloerection, tremors, dyspnea, hypersensitivity to touch and tonic clonic convulsions were observed in all the animals within 4h30 of treatment. Lateral recumbency was also noted in 1/3 animals 3 hours after treatment. In view of these signs of poor clinical conditions, all three animals were sacrificed on day 1 for ethical reasons.

In the repeated toxicity study (OECD 422) the kidney and liver effects are indication of systemic toxicity and therefore of oral absorption.