Ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Assessment of the toxicokinetic behavior of

ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate (CAS No. 115895-09-5)

 

There were no studies available in which the toxicokinetic properties of ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate were investigated. Whenever possible, the toxicokinetic properties of the substance was assessed, taking into account the available information on physico-chemical and toxicological characteristics, according to ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2008).

Ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate (molecular weight of 502.2 g/mol) is a white powder with very low water solubility (0.078 mg/L). According to the Lipinski rule of five, a molecular weight above 500 and log Pow > 5 indicates that a substance has negligible oral bioavailability. The dissociation constant pKa1 is -5.95 at 20 °C, as calculated with SPARC (Karickhoff, 2009). At intestinal pH values the substance will be present in a not ionized form, which favors intestinal absorption. The log Pow is > 9.3, indicating that the fraction of absorbed test substance has the potential to accumulate in fat tissue.

 

Absorption

In an acute oral toxicity study (performed according to OECD 401), rats were administered ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate by gavage (Spanjers, 1988a). The LD50 was determined to be > 5000 mg/kg bw. No mortality occurred and no treatment-related gross pathological effects were observed. Sluggish behavior was noted in all the animals until 4 hours after dosing, while piloerection was observed up to 24 hours after dosing, indicating that the test substance is absorbed. No effects were observed in a reproduction/developmental toxicity screening study performed according to OECD 421, during which males were exposed for 28 days and females for up to 56 days to 30, 150 and 750 mg/kg bw/day test substance by gavage (Fláškarová, 2011). A 28-day repeated dose toxicity study (OECD 407) was performed in rats administered up to 12250 ppm in feed, equivalent to 1419 mg/kg bw/d for males and 1373 mg/kg bw/d for females (Jonker and Lina, 1988). The only treatment-related clinical signs were noted in 2/5 males in the high-dose group that had convulsions lasting around 1 minute on 2 and 4 separate days during the study period, respectively. The lack of unequivocal acute systemic effects at dose levels from 1373 mg/kg bw/day, together with the low water solubility of the test substance and the Lipinski rule of five, suggests limited bioavailability in the gastrointestinal tract. However, treatment-related effects in both sexes in the highest dose group (several haematological parameters, a decrease in the alkaline phosphatase level in the highest dose group) and histopathological effects in the liver of males in the highest dose group, suggests that some of the substance will be absorbed following oral administration. In conclusion, toxicologically relevant effects were limited to doses from 1419 mg/kg bw/day for male rats and 1373 mg/kg bw/day during repeated exposure. 

 

Ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate has a high fat solubility (87.1 g/100 g fat), which facilitates dermal uptake. The topical administration of the substance in an acute dermal toxicity study (Spanjers, 1988b) led to the same, rapid effects as those seen after oral administration. All the animals were moderately sluggish from 1 up to 4 hours after application of the test substance and piloerection was observed at the 24-hour reading time point. This indicates that the substance is likely to penetrate the skin (up to 100%) following exposure to 2000 mg/kg bw/day. 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 (Prinsen, 1988a; Prinsen 1988b; Prinsen, 1989).

 

Due to the low water solubility, an accurate vapour pressure could not be determined. The vapour pressure was measured as 1.6 x 10 -8 Pa at 25 °C (van Hooidonk, 1989), indicating that exposure due to evaporation is not likely. As the substance is a powder with an inhalable fraction (98.7% < 100 µm), exposure via the inhalative route is possible. Because less than 3% of the particles are smaller than 4 µm, very few of the particles are expected to reach the lungs (bronchioles). 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 negligible.

 

Metabolism

Because the oral absorption percentage is predicted to be low, as indicated by the Lipinski rule of five and the results of the oral single and repeated dose exposure studies, the amount of test substance that will be available for metabolism is limited. The results of the 28-day repeated dose toxicity study (Jonker and Lina, 1988) do not show increasingly severe and thus cumulative effects, which indicates that the substance is metabolized within a relatively short time. Therefore, despite the potential of the test substance to accumulate in fat tissue that is predicted by the molecular structure, the study results show that, in practice, the probability of adverse effects due to accumulation in fat tissue is negligable. The potential metabolites following enzymatic metabolism of ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate were predicted using the QSAR OECD toolbox (OECD, 2011). 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. Eighteen hepatic metabolites were predicted. The 22 metabolites that were predicted to form inthe skin are the same, or highly similar, to those expected in the liver. Primarily, an oxygen-carbon bond is broken (hydrolysed), resulting in a fatty acid or alcohol plus the benzene ring. The alcohols are oxidized to the corresponding fatty acids and all fatty acids are further metabolized via β-oxidation in a well-established metabolic pathway (www.kegg.com). The benzene ring with an ester group will probably be conjugated in phase II-reactions and then be excreted. It is likely that the metabolites with a molecular weight < 300 will be excreted via the urine, and the larger ones via the bile. 

The unabsorbed fraction will be metabolized by intestinal bacteria, also to molecules with increased water solubility, and excreted via the faeces.

There is no indication that ethyl 3,5-dichloro-4-hexadecyloxycarbonyloxybenzoate is activated to reactive intermediates under the relevant test conditions. The studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Bednáriková, 2010; Wilmer, 1998a; Wilmer, 1998b). The result of the skin sensitisation study was likewise negative (Prinsen, 1989).

 

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 and metabolised, the majority of the metabolites has a molecular weight below 300 and will most likely be excreted via the urine. Larger molecules will generally be excreted via the faeces.

Reference list

ECHA. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. May 2008. Downloaded from:

http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm?time=1284647204

 

Karickhoff, S.W. (Ed.) SPARC Online calculator, v4.5.1522, 2009. University of Georgia, USA. Calculation performed 07 October 2011. http://archemcalc.com/sparc/

 

OECD. (Q)SAR Toolbox (v2.1, 2011). Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 06 October 2011.

http://toolbox.oasis-lmc.org/?section=overview