Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

No studies are available. The molecular structure, molecular weight, physico-chemical properties incl. water solubility and octanol-water partition coefficient of AF-654 do not favour oral, inhalative and dermal absorption. Distribution might occur to a certain extent. For the fraction of AF-654 that may be absorbed, it is likely that the parent substance will be metabolized in the liver and rapidly excreted via bile and/or urine. Unabsorbed AF-654 will be excreted via the faeces.

Key value for chemical safety assessment

Additional information

There were no studies available in which the toxicokinetic properties of 2-Hexyl-2 ‘-hydroxy-5 ‘-methyldecananilide (AF-654) were investigated. Therefore, the toxicokinetic behavior of the substance has been assessed taking into account the available information on physicochemical and toxicological characteristics, according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance” (ECHA, 2012).

AF-654 (molecular weight of 361.56 g/mol) is a white powder, which is considered insoluble in water (< 0.02 mg/L) due to the presence of strongly apolar groups. It has a log Pow of 8.4, and the vapour pressure is 0.009 Pa at 20 °C.

Absorption

Oral: An acute oral toxicity study in rats (performed according to OECD Guideline 423 and GLP) did not show mortalities or gross pathological abnormalities at the limit dose of 2000 mg/kg bw (Hooiveld, 2003a). Clinical signs were limited to the first 3 days after dosing and included lethargy, hunched posture, uncoordinated movements and piloerection in all animals. In addition, all males showed ptosis on Day 1. A LD50 cut-off value of 5000 mg/kg bw was derived. In a sub-acute 28-day oral repeated dose study performed according to OECD Guideline 407, male and female rats were dosed up to 1000 mg/kg bw/day. No mortality, relevant clinical signs or treatment-related effects on body weight, food consumption, haematology, clinical chemistry, and neurobehaviour, were observed. No treatment-related effects were observed during the gross and histopathological examinations (van Otterdijk, 2004b).

Due to its very low water solubility (< 0.02 mg/L) and its high lipophilicity (log Pow = 8.4) AF-654 is expected to have limited oral absorption (ECHA, 2012). In general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract. In the presence of food and bile salts the solubility might be changed. AF-654 may be taken up by micellar solubilization due to its high partition coefficient (log Pow = 8.4) and enter the systemic circulation via the lymphatic system (ECHA, 2012). However, in general it is assumed and supported by the acute and repeated dose studies that the oral bioavailability and thus the systemic bioavailability of AF-654 will be low.

Inhalation: The vapour pressure of AF-654 is low (0.009 Pa at 20 °C) indicating that exposure due to evaporation is unlikely. As AF-654 is a powder with an inhalable fraction (MMAD: 59.19 µm), exposure via the inhalative route is possible. However, as less than 25% of the particles are smaller than 8.831 µm only few of the particles are expected to reach the lungs (bronchioles) (WHO, 1999). Most of the particles will be trapped on the mucous membrane in the trachea and bronchi, from where they will be transported by ciliary movement upwards to the throat and be swallowed or coughed out. Based on these data, the absorption of the substance via the inhalative route is considered to be low.

Dermal: In an acute dermal toxicity study (OECD Guideline 402, limit test) 2000 mg/kg bw of AF-654 was administered to rabbits (van Otterdijk, 2004a). There was no mortality and no effect on body weight during the 14-day observation period. Hunched and flat posture and/or chromodacryorrhoea were noted in the majority of animals during Day 1-5. The necropsy and gross pathological examination did not reveal any treatment-related effects, which indicates very low dermal toxicity. Due to its high lipophilicity (log Pow = 8.4) uptake into the stratum corneum and transfer between stratum corneum and epidermis is likely to be very slow. Additionally, the low water solubility (< 0.02 mg/L) suggests that dermal uptake in general is low. Moreover, QSAR calculations, which are based on molecular weight, log Pow and water solubility predicted a low absorption rate of 0.796 µg/cm²/h (EPA, 2011). Together with the animal study result these values suggest that dermal absorption for AF-654 is considered to be very low.

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small-water soluble molecules and ions will diffuse through aqueous channels and pores. If the molecule is lipophilic (log Pow > 0), it is likely to distribute into cells (ECHA, 2012). Taking the physico-chemical parameters of AF-654 into consideration, distribution of the absorbed fraction and retention in fatty tissues might occur to a certain extent due to the high lipophilicity (log Pow = 8.4) of the compound, but may be limited by the water insolubility.

 

Metabolism

For the fraction of AF-654 that is absorbed, cleavage of the ester bond is theoretically possible. The potential for enzymatic metabolism of the substance was therefore predicted using the QSAR OECD Toolbox v3.1 (OECD, 2013). The metabolism and resulting metabolites is modelled for enzymes in the liver and the skin, and by intestinal bacteria in the GI-tract. 17 possible liver and skin metabolites were predicted with the OECD Toolbox, including the cleavage products after hydrolysis of the amide group and various hydroxylation products.There is no indication that AF-654 is activated to reactive metabolites under the relevant test conditions. No elevated toxicity was observed after oral treatment, nor were there evidence for differences in toxic potencies due to metabolic changes in in vitro genotoxicity tests.

Studies on genotoxicity (gene mutation in bacteria, chromosomal aberration and gene mutation in mammalian cells) were negative; with and without metabolic activation (Buskens, 2003; Buskens, 2004; Lazová, 2013). Therefore it is unlikely that the test substance or its metabolites will be activated to reactive intermediates under the relevant test conditions. The result of the skin sensitisation study was likewise negative (Hooiveld, 2003d).

Excretion

The fraction of the test substance that is not absorbed via the gastrointestinal tract will be excreted via the faeces. In the fraction that is absorbed, both the unmetabolised part and the metabolites have a molecular weight below 300 and will most likely be excreted via the urine.

 

References

ECHA, 2012. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, European Chemicals Agency, Helsinki. 2012.

 

OECD, 2013. (Q)SAR Toolbox v3.1. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 26 August 2013.http://toolbox.oasis-lmc.org/?section=overview

 

US EPA, 2011. Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10. United States Environmental Protection Agency, Washington, DC, USA. Calculation performed 26 August 2013.

 

WHO, 1999. Hazard Prevention and Control in the Work Environment: Airborne Dust. Occupational and Environmental Health Department of Protection of the Human Environment, World Health Organization, Geneva. 1999. WHO/SDE/OEH/99.14.