Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The substance causes systemic effects upon repeated oral dosing which indicates systemic uptake via this route. Considering the physico-chemical properties, uptake is also expected for skin contact and inhalation. The substance offers several sites for phase I metabolism and is predicted to be non bioaccumulating.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The test item is solid has a molecular weight of 380.5 g/mol. It is not susceptible to acid-catalysed hydrolysis as shown in the hydrolysis study (OECD 111) at pH 4 and it is therefore expected to be stable in the stomach.

Water solubility and log Pow are dependent on pH since the molecule has a tertiary amine function that can become protonated. Solubility in water is generally low, but highest at acidic pH. The log Pow of 4.1 at neutral pH  indicates a low potential for bio-accumulation. 

The particle size distribution of the marketed substance shows that inhalation of the substance is possible during dust forming processes. Exposure to vapour is not relevant since the substance is not handled at elevated temperatures.

The relatively low water and high fat solubility as well as the moderate molecular weight suggest reasonably good uptake of the substance via all routes of exposure. 

Although not relevant for biological activity, it is noted that the substance is designed to undergo photo-cleavage and that the experimental data was performed with measurements to protect against photodegradation in the test system.

 

The substance is neither mutagenic nor does it exhibit a skin sensitizing potential, indicating that it is of low reactivity with biological material in the chemical state of the parent molecule. In a 28-day oral (gavage) toxicity study in rats doses of 150 to 450 mg/kg body weight caused dose-dependent adverse effects in the animals. No neurotoxic signs were recorded, and no clinical signs were recorded towards the end of the treatment period, which indicates that no cumulative effects occurred during this 28-day treatment period. The mean body weight of the high dose group animals was suppressed, and during the recovery period only partial improvement took place. After the 14-day recovery period all those parameters, which are known to recover rapidly, did recover, while lower red blood cell counts are known to require a longer time to recover.  Clinical biochemical parameters recovered fully apart from gamma-glutamyl transferase, which remained elevated. At the end of the treatment period small testes were observed combined with reduced spermatogenesis. These effects were not fully recovered after the treatment-free period, but are considered to be reversible over a longer period of time. Based on the observed findings, it can reasonably be assumed that the test substance was absorbed rapidly. Whether the product was metabolized in the rats is unclear, but elimination seems almost as rapid as uptake as judged from the lack of accumulation phenomena in the second part of the dosing period. 

 

Major possible routes of metabolism are hydroxylation of the benzene rings and opening of the morpholino unit by hydrolysis and subsequent glucuronidation of the hydroxyl group.