Fatty acids, coco, esters with oxybis(propanediol)

Endpoint summary

Description of key information

Assessment of the Toxicokinetic Behaviour

Fatty acids, coco, esters with oxybis(propanediol) (CAS-No. 85711-49-5; EC-No. 288-309-9)

 

There are no studies available in which the toxicokinetic properties of Fatty acids, coco, esters with oxybis(propanediol) were investigated.

 

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance Fatty acids, coco, esters with oxybis(propanediol) was conducted based on the relevant available information.

 

This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012) and taking into account further available information on 2,3-Dihydroxypropyl oleate (CAS 111-03-5), octanoic acid, monoester with glycerol (CAS 26402-26-6) and SALATRIM (an UVCB ofstructured triacylglycerols of Short-and long-chain acyl triglceride molecules prepared by interesterification of triacetin, tripropionin, or tributyrin, or their mixtures with either hydrogenated canola, soybean, cottonseed, or sunflower oil) from which data was used for read-across to cover data gaps.

 

Fatty acids, coco, esters with oxybis(propanediol) (molecular weight of an UVCB is not available, but estimated to 348.48 – 715.09 g/mole) is a light yellowish clear liquid, which is insoluble in water. It only forms emulsions (preliminary test,see chapter 4.8 water solubility). The calculated log Po/w is 2.75 (QSAR estimationKOWWIN v1.68, see chapter 4.7 partition coefficient), indicating lipophilie and that a general accumulation of Fatty acids, coco, esters with oxybis(propanediol) is possible. The vapour pressure of 0,00037 Pa at 20 °C (key study, see chapter 4.6 vapour pressure) is very low.

 

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, 2012).

 

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2012). As the molecular weight of ca. 72% of the Fatty acids, coco, esterswith oxybis(propanediol) is above 500 g/mol absorption of these molecules in the gastrointestinal tract is not very likely. The smaller molecules will be taken up but their content is only ca. 28%.

In the gastrointestinal tract (GIT) metabolism prior to absorption via enzymes of the microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpenhein, 1972a). On the contrary, lower rate of enzymatic hydrolysis in the GIT were shown for compounds with more than three ester groups (Mattson and Volpenhein, 1972a,b).

The available data on oral toxicity of the structurally related substances are considered for the assessment of oral absorption. An acute oral toxicity study is available for 9-Octadecenoic acid, (9Z )-, 2,3-dihydroxypropyl ester (CAS 111-03-5; EC 203-827-7).

In an acute oral toxicity study, female rats were administered the structurally related substance 2,3-dihydroxypropyl oleate (CAS 111 -03 -5) by gavage. No mortalities nor clinical signs of toxicity (no abnormalities in general condition, body weight or gross pathological findings in any animal) were observed at the dose of 2000 mg/kg bw (key, Single Dose Oral Toxicity Test of 2,3-Dihydroxypropyl 9-cis-octadecenoate in Rats, Bozo Research Center Inc, Japan, 2005, see chapter 7.2.1 acute oral toxicity).

No signs of toxicity of the structurally related substance 2,3-dihydroxypropyl oleate were also reported in the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity ScreeningTest in rats. The NOAELs for repeated dose toxicity are considered to be 1000 mg/kg/day or more for parental animals of both sexes under the test conditions (OECD 422 supporting study; see chapter 7.5.1 repeated dose oral).

A sub-chronic toxicity study (90 d) in rats with the structurally related substance SALATRIM indicates that it is well tolerated and does not produce toxicologically significant effects in rats. While macroscopically, no treatment-related effects were observed in SALATRIM-treated rats, there were some minor effects microscopically indicating bioavailability after oral administration.

Therefore, bioavailability of Fatty acids, coco esters with oxybis(propanediol) after oral administration is indicated.

 

The above described studies show that the structurally related substances revealed a low potential for toxicity after acute and repeated exposure, although no assumptions can be made regarding the absorption potential based on the experimental data.

In general, after oral ingestion, Fatty acids, coco esters with oxybis(propanediol)will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. Oxybis(propanediol) (CAS 59113-36 -9; EC 261-605-5) as well as the fatty acids will be formed. Although Fatty acids, coco esters with oxybis(propanediol) have maximal three ester groups it is assumed that they are hydrolysed slowly as well.

The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.

The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). Oxybis(propanediol) (Diglycerol), on the basis of its physical-chemical properties (molecular weight 166.17g/mol, log Pow -2.5, water solubility > 1000 g/L; Pubchem open chemistry database), will readily dissolve into the gastrointestinal fluids.

In summary, the above discussed physical-chemical properties of Fatty acids, coco esters with oxybis(propanediol)and relevant data from available literature do not indicate rapid hydrolysis before absorption of Fatty acids, coco esters with oxybis(propanediol). On the basis of the above-mentioned data, a low absorption of the parent substance is assumed.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of ca. 72% of the Fatty acids, coco esters with oxybis(propanediol)is above 500 g/mol and none of the esters has a molecular weight below 100 g/mol only a very small amount of the UVBC will be absorbed by skin.

 

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). Read-across performed with the substance octanoic acid, monoester with glycerol (CAS 26402-26-6) shows that the test substance is not considered as skin irritating in humans (Acute dermal irritation test in the rabbit,see chapter 7.3.1 skin irritation). Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.

 

In an acute dermal toxicity study a single dose level of 2000 mg/kg Fatty acids, coco esters with oxybis(propanediol) was administered to Sprague-Dawley rats (key study, see chapter 7.2.3 acute dermal toxicity). No signs of systemic toxicity were observed, indicating primarily a low dermal toxicity (the LD50 value of the test item is more than 2000 mg/kg body weight).

Due to the experimental low acute oral and dermal toxicity, no assessment of the dermal absorption potential ofFatty acids, coco esters with oxybis(propanediol) in humans can be made.

 

Overall, due to the experimental low dermal toxicity, the low water solubility, the high molecular weight (>100), the log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, coco esters with oxybis(propanediol) in humans is considered as very low.

Inhalation

 

Fatty acids, coco, esters with oxybis(propanediol) have a very low vapour pressure of 0,00052 Pa at 25 °C (key study, see chapter 4.6 vapour pressure), 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 vapours, gases, or mists is not expected to be significant.

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, 2012).

Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and acid available for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption.

Therefore, respiratory absorption of Fatty acids, coco, esters with oxybis(propanediol) is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of Fatty acids, coco, esters with oxybis(propanediol) in humans is considered likely after inhalation but not expected to be higher than following oral exposure.

Accumulation

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. (ECHA, 2012).

However, as absorption of Fatty acids, coco, esters with oxybis(propanediol) is considered to be low, the potential of bioaccumulation is low as well.

Nevertheless, as further described in the section metabolism below, esters of oxybis(propanediol) and fatty acids will undergo esterase-catalyzed hydrolysis, leading to the cleavage products respective alcohol and the fatty acids.

The log Pow of the first cleavage product oxybis(propanediol) is -2.5 and it is highly soluble in water (1000 g/L) (Pubchem open chemistry database). Consequently, there is no potential for oxybis(propanediol) to accumulate in adipose tissue. The other cleavage products, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance and cleavage products is anticipated.

 

Distribution

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, 2012).

Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rate of absorption.

As discussed above absorption of Fatty acids, coco, esters with oxybis(propanediol) is considered low based on its physico-chemical characterisation as poor water solubility and high molecular weight.

Nevertheless, esters of Fatty acids, coco, esters with oxybis(propanediol) will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products oxybis(propanediol) and the different fatty acids.

Oxybis(propanediol) indicates with its relatively small molecular weight (166) and the high-water solubility (>1000 g/L) that uptake can take place through aqueous pores. However, the hydrophilic character of diglycerol (log Po/w -2.5) will limit this passive diffusion. Overall, it is likely that diglycerol is absorbed from the gastro-intestinal tract. For risk assessment purposes, oral absorption of oxybis(propanediol) is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Distribution of oxybis(propanediol) throughout the body is expected based on its relatively low molecular weight, and accumulation in the body will be limited based on its hydrophilic character. Based on its hydrophilic character, extracellular concentration is expected to be higher than intracellular concentration. Absorbed oxybis(propanediol) might undergo conjugation. The conjugates will either be excreted via the bile (high molecular weights compounds) or the urine (low molecular weight compounds).

The fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977).

Overall, the available information indicates that the cleavage products, oxybis(propanediol) and fatty acids can be distributed in the organism.

 

Metabolism:

 

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

Thus, Fatty acids, coco, esters with oxybis(propanediol) is probably hydrolysed to the corresponding alcohol (oxybis(propanediol) and fatty acids by esterases.

The first cleavage products, fatty acids are stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively.

The other cleavage product oxybis(propanediol) is due to its physico-chemical properties (low molecular weight, low log Pow, and solubility in water) easily absorbed and can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to polar products that are excreted in the urine.

In the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with the structurally related substance 2,3-dihydroxypropyl oleate rats showed no signs of toxicity. The NOAELs for repeated dose toxicity are considered to be 1000 mg/kg/day or more for parental animals of both sexes under the test conditions (OECD 422 supporting study; see chapter 7.5.1 repeated dose oral).

A sub-chronic toxicity study (90 d) in rats with the structurally related substance SALATRIM indicates that it is well tolerated and do not produce toxicologically significant effects in rats. Macroscopically, no treatment-related effects were observed in SALATRIM-treated rats. Microscopically, an increased incidence of mineralization was noted in the kidneys of females fed 5 % and 10 % SALATRIM 234CA lot A019 when compared with the incidence in control females. A slightly higher incidence of renal mineralization also was noted for females fed 5 % and 10 % SALATRIM 234CS lot A018 compared with controls. Except for the 10% SALATRIM 234CA lot A019-treated groups, the mineralization was similar in appearance in all groups. In the 10% SALATRIM 234CA lot A019 females, the severity of this mineralization was slightly greater than in other groups.

Mottled livers and hepatocellular vacuolation were noted for males in the 10 % corn oil group. No hepatic effect was observed in SALATRIM-treated rats.

Serum and liver concentrations of vitamin E in SALATRIM treated rats were comparable to those of control rats. Mean serum vitamin A was significantly higher than control in male rats fed 2 % SALATRIM 234CA lot A019 and 10 % corn oil.

Mean liver vitamin A was significantly lower than controls in 10% SALATRIM 234CA lot A019 males and 10 % SALATRIM 234CS lot A018 and 10 % corn oil males and females.

Mean serum 25-hydroxy vitamin D concentrations were lower than control in females fed 2 % and 10 % SALATRIM 234CA lot A019, 2 % and 10 % SALATRIM 234CS lot A018, and 10% corn oil. These lower values were statistically significant for the 2 % SALATRIM 234CA lot A019 and 2% and 10% SALATRIM 234CS lot A018 groups. No differences in serum 25-hydroxy vitamin D levels were detected in males.

Prothrombin time, an indicator of vitamin K status, was unaffected by exposure to the SALATRIM fats and corn oil.

Viral antibody titers were negative at initiation and termination of the study.

Statistically significant lower aspartate aminotransferase levels were noted for females fed 2 % and 10 % 234CA lot A019 and for females fed 2 %, 5 %, and 10 % 234CS lot A018. Serum aspartate aminotransferase was not affected for males in any treatment group. No other changes in serum chemistry variables, including serum lipids, were noted for rats fed the SALATRIM fats.

In this study with SALATRIM 234CA lot A019 and SALATRIM 234CS lot A018, slightly, but not statistically significantly, increased urinary phosphorus clearance was again noted in 10 % SALATRIM treated rats. No other changes in urinary mineral clearance or other urinalysis variables were observed in rats fed either SALATRIM fat.

 

Studies on genotoxicity (Ames-Test, Chromosome aberration test, HPRT-test, UDS-test and micronucleus assay in-vivo with ca. 7000 mg/kg bw/day) with the structurally related substances were negative.

 

The above described studies show that the structurally related substances revealed a low potential for toxicity after repeated exposure. Based on these data and on the properties of the test substance characteristics a low absorption of Fatty acids, coco, esters with oxybis(propanediol) is assumed.

 

Excretion:

 

On the basis of the low absorption data the main route of excretion for Fatty acids, coco, esters with oxybis(propanediol) is expected to be excreted via faeces.

Assuming that hydrolysis for Fatty acids, coco, esters with oxybis(propanediol) takes place fatty acids and oxybis(propanediol) as breakdown products will occur in the body. 

Potential cleavage products, the fatty acid components will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are 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.

The other cleavage product oxybis(propanediol) may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine.