2-hexyldecanoic acid [4-(6-tert-butyl-7-chloro-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl)phenylcarbamoyl]methylester

Endpoint summary

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 UM-235 do not favour oral, inhalative and dermal absorption. Distribution might occur to a certain extent. For the fraction of UM-235 that may be absorbed, cleavage of the ester bond might theoretically be possible. Unabsorbed and absorbed UM-235 will mainly be excreted via the faeces. 

Additional information

There were no studies available in which the toxicokinetic properties of 2-hexyldecanoic acid [4-(6-tert-butyl-7-chloro-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl)phenylcarbamoyl]methylester (UM-235) 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, 2012a).

UM-235 (molecular weight of 586.22 g/mol) is a white powder, which is insoluble in water (< 0.004 mg/L). It has a log Pow of 8.45 and the vapour pressure is 0.006 Pa at 20 °C.

 

Absorption

Oral: An acute oral toxicity study in rats (performed according to OECD 423 and under GLP conditions) did not show mortalities or gross pathological abnormalities at the limit dose of 2000 mg/kg body weight (Teunissen, 2003a). Clinical signs included hunched posture and piloerection in all animals and females showed uncoordinated movements and one female showed chromodacryorrhoea. All clinical signs were reversed within 3 days. The LD50 was determined to be 5000 mg/kg body weight based on the LD50 cut-off value set according to OECD 423. In a sub-acute 28-day oral repeated dose study performed according to OECD 407, male and female rats were dosed up to 1000 mg/kg bw/day (Hooiveld, 2004b). No mortalities and treatment-related effects on clinical signs, body weight, food consumption, heamatology, clinical chemistry, neurobehaviour, gross- and histopathology were observed.

Due to its high molecular weight (586.22 g/mol), its low water solubility and its high lipophilicity (log Pow = 8.45) UM-235 is expected to have limited oral absorption. 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 somewhat increased. UM-235 may be taken up by micellar solubilization due to its high partition coefficient (log Pow = 8.45) and enter the systemic circulation via the lymphatic system. However, in general it is assumed and supported by the acute and repeated dose toxicity studies that the oral absorption and thus the systemic bioavailability of UM-235 will be low.

 

Inhalation: The vapour pressure of UM-235 is low (0.006 Pa at 20 °C), indicating that exposure due to evaporation is unlikely. As UM-235 is a powder of medium dustiness with an inhalable fraction (90% < 82.86 µm), exposure via the inhalative route is possible. However, 18% of the particles are smaller than 10 µm, and only 1% of these are expected to reach the alveolar region of the lungs (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 403, limit test), 2000 mg/kg bw of UM-235 was administered to rabbits (Hooiveld, 2004a).There was no mortality and no effect on body weight seen during the 14-day observation period. Hunched and flat posture, chromodacryorrhoea (snout), ptosis and diarrhea were noted in the majority of animals up to 2 days after dosing. The necropsy and gross pathological examination did not show any treatment-related effects. No systemic effects were observed after the topical application of up to 0.5 g in the irritation and sensitisation studies, or following instillation in the eye of 0.1 mL during the eye irritation study (Teunissen 2003b; 2003c).

The QSAR tool EpiSuite was applied to calculate the dermal absorption, using the molecular weight, log Pow and water solubility values. A very low dermal absorption rate of 0.0532 µg/cm²/h was predicted (US EPA, 2011). Taking the experimental very low acute dermal toxicity and the calculated very low dermal absorption rate into account, the dermal absorption is considered to be very low. Together with the animal study result these values suggest that dermal absorption for UM-235 will be very low.

 

Distribution

In general, the smaller the molecule, the wider the distribution is expected to be. Small, water soluble molecules and ions will diffuse through aqueous channels and pores. If the molecule is lipohilic (log Pow >0), it is likely to distribute into cells (ECHA, 2012). Taking the pyhsico-chemical parameters of UM-235 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 = 8.45) of the compound, but may be limited by the water insolubility and the high molecular weight.

 

Metabolism

For the fraction of UM-235 that is absorbed, cleavage of the ester bond might theoretically be possible. The potential for enzymatic metabolism of the substance was therefore predicted using the QSAR OECD toolbox (OECD, 2012). This QSAR tool predicts which metabolites of the test substance may be created by enzymes in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. No metabolites were predicted under any of the modelled conditions. 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; Lazova, 2012). 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 (Teunissen, 2003d).

 

Excretion

Due to the molecular weight (>500) and the insolubility in water of the test substance, both the fraction absorbed from the gastrointestinal tract and the unabsorbed fraction of UM-235 is expected to be mainly excreted via the faeces.

 

Reference list

 

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

OECD, 2012. (Q)SAR Toolbox v2.3. 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.