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EC number: 261-332-1 | CAS number: 58567-11-6
There are no studies available in which the toxicokinetic behaviour of (ethoxymethoxy)cyclododecane has been investigated.
Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the substance (ethoxymethoxy)cyclododecane is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014) and taking into account further available information on possible hydrolysis products.
The substance (ethoxymethoxy)cyclododecane is an organic liquid with a molecular weight of 242.4 g/mol. The measured water solubility and log Pow values are 1.12 mg/L at 20 °C and 5.4 at 25 °C, respectively.
Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).
The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). As the molecular weight of (ethoxymethoxy)cyclododecane is 242.4 g/mol absorption of the molecule in the gastrointestinal tract after oral intake is in general anticipated.
Absorption after oral administration of (ethoxymethoxy)cyclododecane is also expected when the “Lipinski Rule of Five” (Lipinski et al. 2001; Ghose et al. 1999) is applied to the substance. Except for the log Pow that exceeds the given cut-off value of 5, all rules are fulfilled, thus, oral absorption is considered to be likely. If absorption occurs, the favourable mechanism will be absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), which are poorly soluble in water (approx. 1 mg/L or less) like (ethoxymethoxy)cyclododecane.
An acute oral toxicity study was performed in rats with (ethoxymethoxy)cyclododecane equivalent or similar to OECD guideline 401 indicating no markedly signs of systemic toxicity resulting in acute oral LD50 value >5000 mg/kg bw (1980a).
Moreover, a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with (ethoxymethoxy)cyclododecane performed according to OECD guideline 422 in rats via the oral route at dose levels of 0, 50, 300 and 1000 mg/kg bw/day is available (2013).
Based on the lesions in the kidneys found in males at the dose levels of 1000 and 300 mg/kg bw/day, which were considered to be adverse, a NOAEL (systemic) of 50 mg/kg bw/day was derived for males. However, the observed lesions in the kidneys were considered to be specific for male rats and therefore considered not to be toxicologically relevant for humans. The NOAEL (systemic) for females was considered to be 1000 mg/kg bw/day due to the absence of any adverse effects. In addition, the NOEL for reproduction/developmental toxicity was considered to be 1000 mg/kg bw/day.
Furthermore, a Prenatal Developmental Toxicity Study was performed with the test substance in rats via the oral route according to OECD guideline 414 (2016). No maternal toxicity and no effects on the number of corpora lutea, implantation sites, live fetuses, sex ratio, resorptions, or pre- and post-implantation losses and fetal body weight were observed. Moreover, no incidences of major malformations or minor external or internal anomalies, skeletal anomalies or skeletal variants that were related to the treatment with the test substance were recorded at any dose level up to and including the highest dose level of 1000 mg/kg bw/day. Taken together, there was no evidence of embryo lethality, fetotoxicity or teratogenicity at dose levels up to 1000 mg/kg bw/day. Thus, the NOAEL for maternal/embryo-/fetotoxicity/teratogenicity in rats was found to be ≥1000 mg/kg bw/day for the test substance.
Overall, the available data indicate low systemic toxicity. The observed test-substance-related effects in the kidney of male rats in the subacute repeated dose toxicity study (2013) lead to the conclusion that the test substance is bioavailable after oral application. However, these effects were considered to be specific for male rats and therefore considered not to be toxicologically relevant for humans.
The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2014). As the molecular weight of (ethoxymethoxy)cyclododecane is 242.4 g/mol dermal absorption of the molecule is considered to be likely.
For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2014). As the water solubility of (ethoxymethoxy)cyclododecane is 1.12 mg/L and the log Pow is 5.4, dermal uptake is likely to be limited. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). An in vivo skin irritation study with (ethoxymethoxy)cyclododecane revealed skin irritating properties (1994).
In addition, an acute dermal toxicity study in rabbits was performed with (ethoxymethoxy)cyclododecane equivalent or similar to OECD guideline 402 demonstrating no signs of systemic toxicity resulting in an acute dermal LD50 value >5000 mg/kg bw (1980b).
Furthermore, QSAR based dermal permeability prediction (Episuite 4.1, DERMWIN V2.02.2012) using molecular weight, log Pow and water solubility for (ethoxymethoxy)cyclododecane was performed resulting in a dermal penetration rate of 0.286 µg/cm²/h for (ethoxymethoxy)cyclododecane. This value is considered as an indicator for a low to medium dermal absorption rate (20%) for (ethoxymethoxy)cyclododecane.
Overall, the low water solubility, the low molecular weight, the high log Pow value and the fact that the substance is considered to be irritating to skin implies that the substance penetrates the skin to some extent. This assumption is supported by QSAR based dermal permeability prediction and the LLNA test (2012a), since the substance showed sensitizing potential after dermal application. However, due to the low toxicological potential of the substance, no clinical signs could be observed after dermal exposure (1980b).
(Ethoxymethoxy)cyclododecane has a measured low vapour pressure of 0.296 Pa at 25 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapors, gases, or mists is not expected.
However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2014).
Lipophilic compounds with a log Pow >4, that are poorly soluble in water (approx. 1 mg/L or less) like (ethoxymethoxy)cyclododecane may be taken up by micellar solubilisation.
Overall, a systemic bioavailability of (ethoxymethoxy)cyclododecane in humans cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm, but is not expected to be higher than following oral exposure.
Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The log Pow of 5.4 implies that (ethoxymethoxy)cyclododecane may have the potential to accumulate in adipose tissue (ECHA, 2014). Absorption is a prerequisite for accumulation within the body. As absorption of (ethoxymethoxy)cyclododecane is anticipated, the potential of bioaccumulation is considered to be likely as well.
Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2014). Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.
For blood : tissue partitioning a QSPR algorithm has been developed by De Jongh et al. (1997) in which the distribution of compound between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol : water partition coefficient (Kow) is described. Using this value for (ethoxymethoxy)cyclododecane predicts that it will distribute into the main body compartments as follows: fat >> brain > liver > kidney > muscle with tissue : blood partition coefficients of 113.9 for fat and 15.3 to 5.5 for the remaining tissues.
Table 1: Tissue : blood partition coefficients
Overall, the available information indicates that (ethoxymethoxy)cyclododecane is assumed to widely distribute throughout the body after absorption and it is likely to distribute into cells of fatty tissues.
No data are available describing the metabolism of (ethoxymethoxy)cyclododecane. However, metabolism of (ethoxymethoxy)cyclododecane is considered negligible, since abiotic and enzyme independent hydrolysis is predicted to be the prominent degradation reaction, leading to the theoretically possible hydrolysis products cyclododecanol and ethoxymethanol.
A hydrolysis study with (ethoxymethoxy)cyclododecane performed according to OECD guideline 111 was conducted. The hydrolysis was studied at pH 4, pH 7 and pH 9 with sample solutions being maintained at 50 and 60 °C. As the substance showed abnormal behaviour with faster hydrolysis at lower temperature, the hydrolysis was directly assessed at 25 °C. It was found that the substance was hydrolysed under all test conditions and that the reaction followed pseudo-first order kinetics. The half-lives for the reaction at 25 °C were calculated from the experimental data and were 299, 259 and 243 hours for pH 4, pH 7 and pH 9, respectively. However, no qualitative or quantitative determination of hydrolysis products was performed.
Overall, the part of (ethoxymethoxy)cyclododecane that has become systemically available, might be hydrolysed and the theoretically possible cleavage products can be further metabolized.
(Ethoxymethoxy)cyclododecane is predicted to undergo very slow hydrolysis as discussed in the metabolism section with half-lives of 299, 259 and 243 hours for pH 4, pH 7 and pH 9, respectively. The theoretically possible hydrolysis products cyclododecanol and ethoxymethanol are predicted to be far more water soluble than the parent chemical and have a molecular weight lower than 242.4 g/mol. Therefore, they are expected to be excreted predominantly via the renal route, whereas the parent chemical is expected to be excreted via feces.
De Jongh et al.(1997): A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch. Toxicol. 72, 17-25
ECHA (2014): Guidance on information requirements and chemical safety assessment, Endpoint specific guidance. European Chemicals Agency, Helsinki
Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.
Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.
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