Fatty acids, coco, esters with 1,3-butanediol

Endpoint summary

Description of key information

Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) is a liquid UVCB substance with low volatility (vapour pressure < 0.001 Pa at 20°C) and a calculated log Pow in the range of 5.22 to >10. Its potential for absorption via inhalation and dermal route is predicted to be low. The substance is expected to be hydrolysed within the gastrointestinal tract. The hydrolysis products (the respective fatty acid and butylene glycol) are predicted to be readily absorbed via the oral route. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons. The major metabolic pathway for linear fatty acids is the beta-oxidation pathway for energy generation. The absorbed butylene glycol is metabolized to acetoacetate and gamma-hydroxybutyrate. The excretion is expected to be mainly as CO2 in expired air. Due to metabolism of the parent substance and the hydrolysis products, bioaccumulation of the parent substance is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Section 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, 2017), assessment of the toxicokinetic behaviour of the target substance Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) was conducted to the extent that can be derived from the relevant available information. This comprised 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, 2017) and taking into account further available information on source substances.

There are no studies available in which the toxicokinetic behaviour of Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) has been investigated. Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) is an UVCB substance specified by mainly C12 (50-60%), C14 (15-25%) C16 (5-15%) and C18 (5-15%) linear fatty acids esterified with 1,3-butanediol resulting in mono- and di-esters. Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) is a liquid at 20°C which has a molecular weight ranging from 272.42 to 623.05 g/mol. Experimental data on water solubility are not yet available (see IUCLID section 4.8), but water solubility was estimated by Dermwin v2.02 to range between 0.002 to 3.25e-016 mg/cm³ for the four main constituents; therefore water solubility of the UVCB substance is expected to be < 1.0 mg/L. The calculated log Pow value is 5.22 to >10 and the vapour pressure was calculated to be < 0.001 Pa at 20°C.

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, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2017).

When assessing the potential of Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) to be absorbed in the gastrointestinal (GI) tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972; National technical information service, 1973). Thus, due to the 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 butylene glycol (1,3-butanediol) and the corresponding fatty acids, mostly C12 and C14. In clinical studies in which volunteers received 50-140 g of coconut oil over 3 days, digestibility was 98% (CIR, 2008).

1,3-butanediol provided as 8% of the total metabolizable energy to pre-partum feeding to sows has been of beneficial effect for survival rate of neonatal pigs (Stahly, 2014); 1,3-butanediol is included in the EU register of flavouring substances used in or on foodstuffs and has been evaluated by EFSA for its use as a flavouring agent (EFSA, 2009d). EFSA concluded that the substance was of no safety concern as a flavouring agent at the estimated level of intake based on the MSDI approach (EFSA, 2009d).

The calculated low water solubility of the constituents (see Table 1) and the high log Pow value > 5.22 indicate that absorption may be limited by the inability to dissolve into GI fluids. However, mi-cellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986). Regarding molecular weight, the breakdown products butylene glycol and 12 to C18 fatty acids are generally favourable for absorption. The alcohol component butylene glycol is water-soluble and has a low molar mass (90.12 g/mol) and can therefore dissolve into GI fluids. Thus, butylene glycol will be readily absorbed through the GI tract. The highly lipophilic fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

In an acute oral toxicity study fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) showed no signs of systemic toxicity resulting in a LD50 value greater than 2000 mg/kg bw (key study, 2004). Furthermore, available data on sub-chronic oral toxicity of the analogue substances 2-hydroxypropyl stearate (CAS 1323-39-3) and C8-C10-1,3-butandiolester (CAS 853947-59-8) showed no adverse systemic effects resulting in NOAEL values of ≥ 1000 mg/kg bw/day. The lack of systemic toxicity of the analogue substances cannot be equated with a lack of absorption but rather with a low toxic potential of glycol esters and the breakdown products themselves.

Dermal

In general, molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2012):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp was calculated for the 4 main constituents of the substance (please refer to Table 1).

Table 1: Dermal absorption values for the constituents of Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) (calculated Oct, 2017 with Dermwin v 2.02, Epiweb 4.1)

Component	Structural formula	Picture	Estimated water solubility [mg/cm³]	Dermal Flux [mg/cm²/h]
1	C16H32O3		0.002	0.00109
2	C22H44O3		1.94e-006	5.58e-005
3	C28H54O4		4.3e-010	6.16e-007
4	C40H78O4		3.25e-016	1.3e-009

 

The calculated dermal flux rates indicate a low dermal absorption potential.

No dermal toxicity studies are available, however the target substance Fatty acids, C12-18, esters with 1,3-butanediol (CAS 73138-39-3) did not cause mortality or adverse clinical signs in an acute toxicity study following oral administration of 2000 mg/kg bw in male and female rats. Furthermore, no systemic effects were noted in the in vivo skin irritation study performed with Fatty acids, C12-18, esters with 1,3-butanediol (CAS 73138-39-3). No dermal toxicity studies are available.

Overall, taking into account the physico-chemical properties of Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3), the QSAR calculations and available toxicological data, the dermal absorption potential of the substance is predicted to be low.

Inhalation

Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) is a liquid at 20°C with low vapour pressure (<0.001 Pa at 20°C (7.5 x 10-6 mmHg), and therefore of low volatility. Under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases or mists is considered to be limited (ECHA, 2017). Based on the uses information, the potential for exposure via the inhalation route and the potential for absorption via inhalation is considered to be low.

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical 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. 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, 2017).

As the parent compound Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) will be hydrolysed prior to absorption (as discussed above); the distribution of the intact substance is of less relevance than the distribution of the breakdown products of hydrolysis. The absorbed products of hydrolysis, butylene glycol and the respective fatty acid moieties can be distributed within the body.

The alcohol butylene glycol has a low molecular weight and high water solubility. Butylene glycol is metabolized by ADH to acetoacetate and gamma-hydroxybutyrate (CIR, 1985). Substances with high water solubility like butylene glycol do not have the potential to accumulate in adipose tissue due to its low log Pow.

Like all medium and long chain fatty acids, the fatty acids may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons or absorbed from the small intestine directly into the bloodstream and transported to the liver. Via chylomicrons, fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994).

Therefore, the intact parent compound is not assumed to accumulate as hydrolysis will mainly take place before absorption and distribution. However, accumulation of the fatty acids in triglycerides in adipose tissue or the incorporation into cell membranes is possible as further described in the metabolism section below. At the same time, fatty acids may also be used for energy generation. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

In summary, the available information on Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected. The hydrolysis products, butylene glycol and the respective fatty acids will be distributed within the organism.

Metabolism

Metabolism of Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. butylene glycol monolaurate and -myristate), the fatty acids moieties (mainly C12 and C14) and butylene glycol.

The hydrolysis of fatty acid esters invivo was studied in rats dosed with fatty acid esters containing one, two (like butylene glycol esters) or three ester groups. The studies showed that fatty acid esters with two ester groups are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson and Volpenheim, 1968; 1972).

Following absorption into the intestinal lumen, fatty acids are re-esterified with glycerol to triacylglycerides (TAGs) and included into chylomicrons for transportation via the lymphatic system and the blood stream to the liver.

In the liver, fatty acids can be metabolised in phase I and II metabolism.

An important metabolic pathway for fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1970; Stryer, 1994).

Butylene glycol (Butane-1,3-diol) is metabolised in the cytosol and converted by the liver to ketones prior to its oxidation in the tricarboxylic acid cycle. Alcohol dehydrogenase acts as catalyst in the catabolism in the cytosol of butane-1,3-diol to an intermediate, aldol. Aldol is then further oxidised to beta-hydroxybutyrate (EFSA 2009d).

Available genotoxicity data from the test substance and structural related analogue substances do not show any genotoxic properties. Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) was tested in an Ames-tests according to OECD guideline 471(key study, 2004), an in-vitro mammalican cell micronucleus test according to OECD guideline 487 (key study, 2018), and an in vitro mammalian gene mutation assay according to OECD guideline 490 (key study, 2018). Results were consistently negative and therefore there is no indication of higher reactivity of metabolites.

Excretion

Based on the metabolism described above, Fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3) and its breakdown products will be metabolised in the body to a high extent. In clinical studies in which volunteers received 50-140 g of coconut oil over 3 days, digestibility was 98%. Coconut oil is typically composed of 90% saturated triglycerides, mainly with C12 and C14 fatty acids, and low in non-glyceride impurities (CIR, 2008).

Butylene glycol (Butane-1,3-diol) is metabolised to beta-hydroxybutyrate (EFSA 2009d), which can be excreted via urine.

The fatty acid components will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above.

References

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CIR (1985). Final report on the safety assessment of Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol.

CIR (2008). Final Report of the Cosmetic Ingredient Review Expert Panel. Amended Safety Assessment of (amongst others) Butylene Glycol Cococate. 23 Sep 2008.

Dymsza HA. Nutritional application and implication of 1,3-butanediol. Fed Proc. 1975 Nov;34(12):2167-70.

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017.

EFSA (European Food Safety Authority), 2009d. Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from Commission on Flavouring Group Evaluation 10 Revision1 (FGE.10 Rev1). Aliphatic primary and secondary saturated and unsaturated alcohols, aldehydes, acetals, carboxylic acids and esters containing an additional oxygenated functional group and lactones from chemical groups 9, 13 and 30. The EFSA Journal, 934, 1-114.

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Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2):428-439.

Mattson F.H. and Volpenhein R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lip Res 9, 79-84.

Mattson, F.H. and Volpenheim, R.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171 -1176

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Stahly TS, Raff DK, Frey GD, Zamzow JB. Efficacy of 1,3-butanediol for enhancement of neonatal pig survival. Anim Reprod Sci. 2014 Aug;148(3-4):145-52.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA. Downloaded from: http://www.epa.gov/oppt/exposure/pubs/episuite.htm