Dodecanoic acid, ester with oxybis[propanediol]

Endpoint summary

Additional information

There are only few studies available in which the toxicokinetic behaviour of polyglycerol esters has been investigated. No toxicokinetic studies are available for the substance Reaction products of lauric acid and oxybis(propanediol).

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006, assessment of the toxicokinetic behavior of the substance Reaction products of lauric acid and oxybis(propanediol) 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, 2008).

 

Absorption

The substance Reaction products of lauric acid and oxybis(propanediol) mainly consists of mono- and diesters of diglycerol and C12 fatty acid (lauric acid) (> 80%). Impurities deriving from the production process are substance-related and include glycerol monolaurate and triglycerol monolaurate as well as free diglycerol and triglycerol residues in varying amounts and each accounting for less than 10% of the substance. The molecular weights of the main components range from 348.47 g/mol (diglycerol monoester) to 530.78 g/mol (diglycerol diester). The diglycerol mono- and diester fractions account for 70-80% and 8-14% of the substance, respectively. The weighted average molecular weight is around 360 g/mol.

The substance Reaction products of lauric acid and oxybis(propanediol) is a pasty solid (at 20 °C), marketed in non-granular form, with very low vapour pressure (< 0.01 Pa) and slight water solubility (11 mg/L). The octanol/water partition coefficients of the main components, mono- and diester of lauric acid with diglycerol, are calculated to be 2.75 and 8.66, respectively.

Based solely on physicochemical properties, absorption rates are anticipated to be low to moderate by the oral route and low by inhalation and through the skin. However, as discussed below, systemic absorption and bioavailability of the substance as such are considered to be low to very low due to enzymatic ester hydrolysis.

Oral

Fatty acid esters of aliphatic alcohols are normally degraded to the corresponding fatty acid and the alcohol by enzymatic hydrolysis in the gastrointestinal tract prior to absorption (Michael & Coots, 1971, Laposata et al., 1990). In this case, the predicted metabolites are the free fatty acid lauric acid (C12) and the polyglycerol diglycerol. Especially esters with fatty acids from C6 to C12 carbon chain length are rapidly hydrolysed in the intestine and the absorption of the resulting free fatty acids is twice faster in comparison to longer chain fatty acids (Henwood et al., 1997). Moreover, data from metabolism studies with fatty acid-labelled polyglyerol esters have shown that more than 90% of triglycerol moieties from respective esters were absorbed (Michael & Coots (1971)). Furthermore, it was shown that hydrolysis of the polyglycerol esters occurred to a large extent prior to absorption. Therefore, absorption of both metabolites; the fatty acid lauric acid and the polyglycerol diglycerol, from the gastrointestinal tract is expected to be high and vice versa a low systemic exposure to the parent compound is expected.

The absorption, distribution, metabolism and elimination of fatty acids have been extensively investigated and are described in the relevant literature (Löffler G, 2007; Berg JM, 2003). It is outside the scope and the aim of this assessment to recapture this information. Therefore, additional information on the relevant metabolites is only given where applicable.

Studies with Reaction products of lauric acid and oxybis(propanediol) after oral administration are not available. However, available oral toxicity data of the structurally related substance 2,3-dihydroxypropyl laurate (CAS No. 142-18-7) are considered for assessment. In the respective study, absence of systemic toxicity was observed with the surrogate substance in the test animals at dose levels up to 20000 mg/kg bw/day (Sterner, 1977). Furthermore, no toxic systemic effects or evidence of absorption were observed in repeated dose toxicity studies after oral exposure to structurally-related substances, which resulted in most cases in short- and long-term oral NOAEL values beyond limit dose values (Yamaguchi; Fitzhugh, 1960; NTP, 2004; Matsuo, 2004; Matulka, 2009). The results of these studies do not allow conclusions on absorption but rather provide evidence for low systemic toxicity of the substance class of fatty acid esters.

In summary, the oral absorption rate of Reaction products of lauric acid and oxybis(propanediol) as such is anticipated to be low, while absorption of the hydrolysis products is considered to be high.

Inhalation

As stated above, the substance Reaction products of lauric acid and oxybis(propanediol) has a very low vapour pressure (0.01 Pa), is a pasty solid at 20°C and is marketed in non-granular form. Moreover, the substance is not used in spraying or brushing applications (no disperse applications).Therefore, human exposure by inhalation is unlikely.

Based on the substance class and physicochemical properties of the main components, applying a conservative approach, the absorption of Reaction products of lauric acid and oxybis(propanediol) via the lung is expected to be at most equal to the oral absorption.

The main components diglycerol monoester and diglycerol diester have a log Pow values of 2.75 and 8.66, respectively. A log Pow value between -1 and 4 favours absorption by passive diffusion. Therefore, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for the diglycerol monoester. The second main component diglycerol diester has a higher log Pow value and may therefore be taken up by micellular solubilisation.

Absorption of the substance, respectively of the metabolites, via the oral route is driven by enzymatic hydrolysis of the ester. Therefore, for effective absorption via the inhalation route enzymatic hydrolysis in the airways would be required first. For effective hydrolysis, the presence of esterases and lipases in the mucus lining fluid of the respiratory tract would be essential; however, due to the physiological function in the context of nutrient absorption, esterase and lipase activity in the lung is expected to be lower than in the gastrointestinal tract. Thus, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to be less effective.

In conclusion, exposure to the substance Reaction products of lauric acid and oxybis(propanediol) by inhalation is unlikely and thus not relevant. In a conservative approach, absorption of the substance as such is considered to be at most equally low as by the oral route.

Dermal

There are no experimental data available on dermal absorption or on acute dermal toxicity of Reaction products of lauric acid and oxybis(propanediol).

As indicated, the substance is a solid paste at 20°C. In general, dry matter is less effectively absorbed than liquids and substances in solution. The molecular weight of the main components suggests a moderate to low skin penetration potential for the diglycerol monoester (348.47 g/mol) and the diglycerol diester (530.78 g/mol), respectively (Bos et al., 2000). With a log Pow of 2.75, dermal absorption is considered to be moderate for the diglycerol monoester. Log Pow values above 6, like for the diglycerol diester (log Pow = 8.66), will slow the rate of transfer between the stratum corneum and the epidermis and therefore absorption across the skin will be limited and uptake into the stratum corneum itself is slow. Considering the water solubility of the substance (11 mg/L) absorption is anticipated to be low. QSAR calculation using EPI Suite DERMWIN v2.01 confirmed this assumption, resulting in a Dermal Flux of 2.83 x 10-4 mg/cm² per h for the main component diglycerol and a Dermal Flux of 4.75 x 10^-7 per h for the diglycerol diester component.

No toxic effects or evidence of absorption were observed in skin and eye irritation and sensitisation studies of structurally-related substances (Koopmans and Daamen, 1989; Guest, 1989; Sterner, 1977a,b; Gloxhuber and Potokar, 1979).

In conclusion, based on the considerations discussed above the overall weight of evidence from physicochemical properties and data on structurally-related substances, the dermal absorption potential of the test substance Reaction products of lauric acid and oxybis(propanediol) is assumed to be low.

 

Metabolism and Distribution

Distribution of the intact parent compound within the body is assumed to be low, as fatty acid esters are normally degraded to the corresponding fatty acid by ubiquitously distributed unspecific esterase and by gastrointestinal lipases prior to absorption. Therefore, distribution of the intact compound is not relevant but rather the distribution of the breakdown products of hydrolysis.

The resulting fatty acid lauric acid belongs to the medium chain fatty acids (6 to 12 carbon fatty acids) and can be distributed within the body. Medium chain fatty acids are assumed to be used in energy metabolism to a higher percentage than fatty acids with longer carbon chain, but are less effectively incorporated into tissue lipids (Henwood et al., 1997).

The -oxidation represents the most relevant metabolic pathway for fatty acids regarding energy generation. In general, the fatty acids are esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria. Thereafter, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by stepwise removal of 2-carbon units from the aliphatic acyl-CoA molecule. The formation of the ultimate products H2O and CO2 takes place via further oxidation in the citric acid cycle (Lehninger, 1970; Stryer, 1996).

The polyol diglycerol is assumed to be rapidly excreted and metabolism via cleavage of the ether bond to glycerol will not occur as shown for the related triglycerol (Michael and Coots, 1971). In the study from Michael and Coots (1971) it was concluded that polyglycerols like triglycerol were not catabolized and that the ether linkages within the molecule are inert to normal enzymatic hydrolysis.

 

Accumulation

The substance Reaction products of lauric acid and oxybis(propanediol) as a whole is not expected to bioaccumulate, although the log Pow of > 2.75 indicates the potential for bioaccumulation of the parent compound in fat tissue. As discussed above, the substance will be hydrolysed prior to absorption, especially after uptake via the oral route, and the lipid component will be used as energy source. Fatty acids of a medium carbon chain length are assumed to be used in energy metabolism to a high percentage, but are less effectively incorporated into tissue lipids (Henwood et al., 1997). However, bioaccumulation of fatty acids can take place, if their intake exceeds the caloric daily requirements of the individual. The polar polyol component diglycerol will not accumulate (Michael & Coots, 1971).

 

Excretion

The polyol diglycerol is assumed to be metabolised only to a low degree and will be excreted almost quantitatively in the urine (Michael & Coots, 1971). The fatty acid component lauric acid will be metabolised in the body for energy generation. Based on the extensive metabolism, the primary route of excretion will be via exhaled air as CO2. Thus, lauric acid is not expected to be excreted to any significant amount via the urine or faeces.

 

References:

Berg JM, Tymoczko JL, Stryer, L. (2003).Biochemie. 5. Auflage. Spektrum, Heidelberg, Berlin.

Bos JD, Meinardi MMHM. 2000.The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 9:165-69.

Henwood S, Wilson D, White R, Trimbo S. 1997. Developmental toxicity study in rats and rabbits administered an emulsion containing medium chain triglycerides as an alternative caloric source. Fundam Appl Toxicol. 40(2):185-90.

Laposata EA, Harrison EH, Hedberg EB. 1990. Synthesis and degradation of fatty acid ethyl esters by cultured Hepatoma cells exposed to ethanol. The Journal of Biological Chemistry 265(17):9688-9693

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Löffler, G et al. (2007). Biochemie und Pathobiochemie. 5th ed. Springer.

Michael WR, Coots RH. 1971. Metabolism of polyglycerols and polyglycerols esters.Toxicology and Applied Pharmacology 20(3):334-345

Stryer, L. (1996). Biochemistry. Fourth edition. Spektrum Akad. Verl.