1,3-butylene diacetate

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 1,3-Butylene diacetate has been investigated.

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, 2008), assessment of the toxicokinetic behaviour of the substance 1,3-Butylene diacetate was 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, 2008) and taking into account further available information on the breakdown products of ester hydrolysis.

The substance 1,3-Butylene diacetate is a diester of 1,3-Butylene glycol and Acetic acid and meets the definition of a mono-constituent substance based on the analytical characterization. 1,3-Butylene diacetate is an organic liquid at 20°C and has a molecular weight of 174.2 g/mol and a water solubility of 100 g/L (Bowdery, 2011; Auty, 2012). The log Pow is calculated to be 1.31 (Müller, 2011) and the vapour pressure is calculated to be 16.61 Pa at 20 °C (Nagel, 2011).

Absorption

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, 2008).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favorable for oral absorption (ECHA, 2008). As the molecular weight of 1,3-Butylene diacetate is 174.20 g/mol, absorption of the intact molecule in the gastrointestinal (GI) tract can be anticipated.

Absorption after oral administration is also expected when the “Lipinski Rule of Five” ((Lipinski, 2001), refined by Ghose (1999)) is applied to the substance 1,3-Butylene diacetate. However, when assessing the potential of 1,3-Butylene diacetate to be absorbed in the GI tract, it has to be considered that esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Nolen, 1972). The hydrolysis of the structurally similar substance Ethylene diacetate (CAS 111-55-7) was determined in an in vitro study using simulated intestinal fluid (Butler, 2013). Following incubation of the test item (1.5 g/L) in the simulated intestinal fluid at 37 °C, the degree of hydrolysis was 4.37, 6.42 and 10.5% after 1, 2 and 4 h, respectively. The rate constant for the reaction was calculated to be 7.42E-06 per sec and the half-life time was estimated to be ca. 26 h. The parent substance and the hydrolysis products are thus anticipated to be present in the GI tract for absorption. Further hydrolysis of the parent substance may occur by endogenous esterase activity mainly in the liver. Due to the anticipated hydrolysis the predictions based upon the physico-chemical characteristics of the intact parent substance alone may no longer apply but also the physico-chemical characteristics of the breakdown products of the ester; the alcohol component Ethylene glycol and Acetic acid (ECHA, 2008).

As 1,3-Butylene diacetate is highly water-soluble, the substance will readily dissolve into GI fluids. The molecular weight of the parent substance 1,3-Butylene diacetate (174.2 g/mol) does suggest absorption as described above. Furthermore, when considering the hydrolysis products 1,3-Butylene glycol and Acetic acid, both are highly water-soluble and have low molecular weights and can therefore dissolve into GI fluids, as well (Acetic acid: miscible; 1,3 Butylene glycol: 1.0E6 mg/L; SRC database). The respective molecular weights of 1,3-Butylene glycol (90.12 g/mol) and Acetic acid (60.05 g/mol) do favour absorption, as well. Due to their low molecular weights, the hydrolysis products and the intact parent substance may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water. Furthermore, the moderate log Pow of the substances favours absorption by passive diffusion (1,3-Butylene glycol: -0.29; Acetic acid: -0.17, SRC database). Thus, 1,3 Butylene diacetate, 1,3 Butylene glycol and Acetic acid will be readily absorbed through the GI tract (ATSDR, 2010; ICPS, 2001; SCOEL, 2012;No. 2000/15OSH/113, 2004; NTP, 1993). Studies investigating the acute oral toxicity of the structurally related substance Ethylene diacetate (CAS 111-55-7) are available resulting in a LD value of > 2000 mg/kg bw (Smith, 1941). The lack of short-term systemic toxicity of the structural analogue Ethylene diacetate cannot be equated with a lack of absorption or with absorption of the 1,3-Butylene diacetate and Ethylene diacetate but rather with a low toxic potential of the substances and the breakdown products themselves.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of 1,3-Butylene diacetate. On the basis of the following considerations, the dermal absorption of 1,3-Butylene diacetate is considered to be high. Regarding the molecular weight of 1,3-Butylene diacetate (174.2 g/mol) dermal uptake of the substance is possible. Regarding the calculated octanol/water partition coefficient of 1.31 (Müller, 2011) together with the high water solubility, dermal absorption is favoured. QSAR calculation using EPIwebv4.1 resulted in a Dermal Flux of 3.42E-1 mg/cm2 per h and QSAR calculation using DERMWIN showed a high dermal absorption potential of 1,3-Butylene diacetate. Available data on acute dermal toxicity of the structurally related substances Propane-1,2-diyl diacetate (CAS 623-84-7), 2-(2-ethoxyethoxy)ethyl acetate (CAS 112-15-2) and 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) did not show signs of systemic toxicity, resulting in LD50 values > 2000 mg/kg bw (e.g. Thouin, 1986). In addition, irritation and sensitisation studies with either the structurally related substance Propane-1,2-diyl diacetate showed no irritating effects to skin and eyes and no signs of systemic toxicity were determined in respective studies. The lack of systemic toxicity of the structurally related analogue substances cannot be equated with a lack of absorption or with absorption of both 1,3-Butylene diacetate or the analogue substances but rather with a low toxic potential of 1,3-Butylene diacetate.

Overall, taking into account the physico-chemical properties of 1,3-Butylene diacetate and the QSAR calculation, the dermal absorption potential of the test substance is anticipated to be high.

Inhalation

1,3-Butylene diacetate has a very low vapour pressure of 16.61 Pa at 20 °C thus being of low volatility (Nagel, 2011). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2008).

Due to the high hydrophilicity of 1,3-Butylene diacetate, deposition in the mucus is possible. Due to the moderate log Pow value 1,3-Butylene diacetate and also of the predicted products of ester hydrolysis 1,3 Butylene glycol and Acetic acid, direct absorption across the respiratory tract epithelium by passive diffusion is favoured. Absorption of deposited material is anticipated to be high, due to the low molecular weight and the moderate log Pow of the parent substance and the hydrolysis products as discussed in the oral absorption section above. Data from acute studies via inhalation and oral route from the structurally related substance Propane-1,2-diyl diacetate (CAS 623-84-7) did not show systemic toxicity. However, this lack of short-term systemic toxicity of the surrogate substance cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of the test substance and the breakdown products themselves. Thus, based on the physicochemical properties of 1,3-Butylene diacetate and data on acute inhalation toxicity of the structurally related substance Propane-1,2-diyl diacetate absorption via the lung is expected to be high.

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution (ECHA, 2008). As the parent compound 1,3-Butylene diacetate will be hydrolysed to a substantial amount before absorption or thereafter in the liver, the distribution of intact 1,3-Butylene diacetate is not solely relevant but also the distribution of the breakdown products of hydrolysis. 1,3-Butylene diacetate and the products of hydrolysis, Acetic acid and 1,3-Butylene glycol can be distributed within the body. Both the parent substance and 1,3-Butylene glycol and Acetic acid have low molecular weights and high water solubilities. Based on the physico-chemical properties, 1,3-Butylene diacetate, 1,3-Butylene glycol and Acetic acid will be distributed within the body (ATSDR, 2010; ICPS, 2001; USEPA HPV, 2002). Substances with high water solubility like 1,3-Butylene diacetate, 1,3-Butylene glycol and Acetic acid do not have the potential to accumulate in adipose tissue due to their low log Pow. In addition, the intact parent compound 1,3-Butylene diacetate is not assumed to be accumulated as hydrolysis to 1,3-Butylene glycol and Acetic acid is anticipated to take place before absorption or during metabolism (see below).

Metabolism

Metabolism of 1,3-Butylene diacetate is expected to occur initially via enzymatic hydrolysis of the ester by ubiquitous expressed esterases before absorption. In in-vivo studies in rats with esters containing Ethylene glycol, it was shown that they are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson and Volpenheim, 1968; Mattson and Nolen 1972). The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). In addition, simulation of intestinal metabolism of 1,3-Butylene diacetate, using the OECD QSAR ToolBox v.2.3.0, resulted in 16 intestinal metabolites including 1,3-Butylene monoacetate, Acetic acid and oxidized 1,3-Butylene glycol derivates (e.g. beta-Hydroxybutyrate) supporting the metabolism pathway of a stepwise ester hydrolysis, as well. Similarly, liver metabolism simulation resulted in 9 metabolites including 1,3 Butylene monoacetate and Acetic acid. Following hydrolysis, absorption and distribution of the alcohol component, 1,3-Butylene glycol will be metabolised. Studies in rats with 1,3-Butylene glycol showed that it is metabolised by alcohol dehydrogenases to beta-Hydroxybutyraldehyde, which is rapidly oxidized to beta-Hydroxybutyrate. Stepwise metabolic conversion will lead to Acetoacetate and Acetyl-CoA, followed by entry of Acetyl-CoA into the Citric acid cycle (USEPA HPV, 2002; Steele, 1982). The second product of hydrolysis, Acetic acid and the respective acetate ion are normally-occurring metabolites in catabolism or in anabolic synthesis, e.g. in the formation of Glycogen, Cholesterol synthesis and degradation of fatty acids (SCOEL, 2012). Available genotoxicity data from the structurally related analogue substances Ethylene diacetate (CAS 111-55-7) and Propane-1,2-diyl diacetate did not show any genotoxic properties. In particular, an Ames test with Ethylene diacetate (Lawlor, 2000), an in-vitro chromosomal aberration test with Ethylene diacetate (Murli, 2000) and an in-vitro mammalian gene mutation assay with Propane-1,2-diyl diacetate (Indrani, 2011) were consistently negative and therefore no indication of a genotoxic reactivity of 1,3-Butylene diacetate is indicated.

Excretion

Based on the metabolism described above, 1,3-Butylene diacetate and its breakdown products will be metabolised in the body to a high extent. Acetic acid and 1,3-Butylene diacetate, will be metabolised in the citric acid cycle and mainly excreted via exhaled air as CO2 (Lehninger, 1970; Steele, 1982; Stryer, 1994; USEPA HPV, 2002).

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.