2-benzyl-2-dimethylamino-4'-morpholinobutyrophenone

Endpoint summary

Description of key information

The substance is taken up after ingestion as shown by systemic toxicity upon subacute gavage dosing. Based on the hazard profile and theoreretical considerations on xenobiotic metabolism as well as physico-chemical properties, bioaccumulation is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No experimental data on toxicokinetic properites are available. The physico-chemistry parameters are not indicative of a bioaccumulation hazard.

The substance has a molecular weight of 366.5 g/mol, a low volatility (vapour pressure 6.10-7 Pa at 25°C), moderate water solubility (5.9 mg/l at 20°C) and an experimental n-octanol-water partition coefficient (log Pow) of 2.91.

Further information is derived from the experimental toxicity data as far as possible:

Adsorption

Repeated subacute oral application to rats caused transient neurological symptoms and a reversible increase in liver and adrenal weight at lower doses with a NOAEL of 100 mg/kg bw. In addition, slight reduction in red blood cell parameters and increased amounts of reducing substances in the urine were observed. In the one-generation reproduction toxicity study in rats, reduced parental body weight and fetal weight plus a low incidence of pup loss due to mortality or small litter size was observed at 300 mg/kg/day. The substance has a low acute oral and dermal toxicity. It is not sensitizing.

Altogether, these observations indicate absorption after oral application. Additionally, the physico-chemical properties of the substance (size, the partition coefficient (2.91) and water solubility) and consideration of Lipinsky’s rule of 5 [Lipinski C., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 46 (2001) 3–26] impose that the compound is orally absorbed.

Inhalation toxicity has not been studied. Absorption via the respiratory tract is predominantly depending on the particle size. The particle size distribution shows a mean diameter of 55 micrometer. It is postulated that only a small proportion of the inhalable substance would reach the deeper respiratory region. Then, adsorption through the alveolar membranes might be possible in view of the bioavailability achieved after oral administration. Local irritation effects however are not expected. Overall, toxicity after inhalation administration would be inferior compared to toxicity obtained after repeated oral administration.

Repeated dermal toxicity has so far not been studied. Dermal absorption is slight to moderate as calculated by the skin penetration model by Fitzpatrick [Fitzpatrick D. Modelling skin permeability in risk assessment––the future. Chemosphere 55 (2004) 1309–1314]. It is expected that toxicity upon dermal application is much lower than upon oral application. Furthermore, local effects can also be excluded.

 

Distribution

It is unlikely to undergo hydrolysis in the stomach; therefore it is postulated that the toxic effects are attributable to the parent compound. It can be assumed that the intact photoinitiator circulates in the blood.

Considering the toxicity on the fetal and newborn rats, it is possible that the substance and/or its metabolites are able to pass the placenta barrier.

In view of the reversibility of effects at the end of a treatment period without administration, accumulation in the body is not expected.

 

Metabolism / Elimination

The absorbed compound is expected to undergo hepatic metabolic degradation of the following kind:

 

- aryl epoxide formation followed by hydroxylation

- keto-hydroxylation

- morpholine ring cleavage and ring opening

 

The tentative metabolic transformation involves the morpholine moiety. Morpholine ring opening catalyzed by a cytochrome-P450-dependent monooxygenase leading to glycolic acid structures has been described for various drugs [Jauch, R.; Griesser, E.; Oesterhelt, G.; Arnold, W.; Meister, W.; Ziegler, W. H.; Guentert, T. W., Biotransformation of moclobemide in humans. Acta Psychiatr Scand Suppl 1990, 360, 87-90; McKillop, D.; McCormick, A. D.; Miles, G. S.; Phillips, P. J.; Pickup, K. J.; Bushby, N.; Hutchison, M., In vitro metabolism of gefitinib in human liver microsomes. Xenobiotica 2004, 34, (11-12), 983-1000].

Morpholine does not bind significantly to plasma proteins and is rapidly eliminated via the renal route as unchanged compound or its cleavage products.