Diisodecyl sebacate

Endpoint summary

Description of key information

In the absence of specific data regarding the ADME of diisodecyl sebacate (DIDS), its physicochemical properties and structural features were assessed for insights into likely ADME characteristics. DIDS has a high MWt (483), low water solubility (<1 mg/L) and high log Pow (>6.5); therefore absorption of intact DIDS via the dermal, inhalation and oral routes is anticipated to be low.. Nevertheless, hydrolysis and uptake of hydrolysis products following ingestion is expected to be extensive, dictating a precautionary approach and thus a default value of 100% absorption is considered appropriate for oral exposure. Limited support for this comes from QSAR analysis (using a model without a defined domain) which suggested that 92% oral absorption may occur. Due to its low vapour pressure, inhalation of DIDS vapours is not expected but a default value of 100% is also proposed for the inhalation route. Based on the high log Pow, a default of 10% for dermal absorption is suggested. Distribution of any absorbed intact DIDS would be expected to be limited by its low water solubility and high MWt but such a scenario is probably unimportant because (a) the major absorbed species are probably hydrolysis products and (b) any absorbed intact diester is likely to undergo rapid and extensive metabolism and utilisation or excretion. Bioaccumulation is not expected.
 
Any non-utilised hydrolysis/metabolic products are likely to be excreted in the urine. Should any DIDS be absorbed intact and survive systemic metabolism, it could be excreted in the faeces via the bile.
 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

ABSORPTION

Oral

No data were identified specifically regarding the oral absorption of DIDS. A QSAR model (HIA Multicase, without a defined domain) within the OECD QSAR Toolbox (OECD, 2012) predicted human intestinal absorption of DIDS to be 92.4%. However, it is unclear whether this model is capable of taking intestinal enzyme action into account. The molecular weight (MWt) (483 Daltons) falls just within the range considered favourable for absorption (<500) (ECHA, 2012a) but, again, this may not take account of pre-absorption metabolic changes in structure.

In fact, absorption of intact DIDS is likely to be low. Factors such as a very low aqueous solubility (about 0.095mg/L) and high log Pow (>6.5) argue against significant absorption of intact DIDS. For a substance to be absorbed efficiently from the gastrointestinal tract it must be in solution. DIDS’s low aqueous solubility means it would not be expected to readily dissolve in gastrointestinal fluids (ECHA, 2012a). Moreover, hydrolysis by gastrointestinal esterases (e. g. pancreatic lipase) is likely to be substantial; these mammalian enzymes (aided by bile salts and phospholipids) are highly efficient at hydrolysing esters, having evolved to aid uptake of dietary triglycerides (which are glycerol-fatty acid triesters). This hydrolysis will lead to the formation of iso-decanol, sebacic acid and the mono-ester (isodecyl sebacate) in the lumen. Gastro-intestinal absorption of n-decanol is rapid and extensive (>80%) (EFSA, 2010) and the same is likely to apply for iso-decanol. The acid and mono-ester can then associate with bile salts and phospholipids to form micelles, which transport these poorly-soluble molecules to the surface of the enterocyte where they can be absorbed. Micelles constantly break down and re-form, feeding a small pool of mono-esters and fatty acids in solution, so that they can then be absorbed.

In conclusion, oral absorption of intact DIDS is expected to be very low due to its physicochemical characteristics and extensive gastro-intestinal hydrolysis. However, absorption of its hydrolysis products (iso‑decanol, sebacic acid and mono-ester) is likely to be extensive, an assumption that is supported by QSAR analysis. In the absence of specific data to the contrary, a precautionary approach has been taken and a default value of 100% absorption of DIDS or, more likely, its hydrolysis products, is proposed.

Relevant read-across data:

DIDA and DEHS/DOS have MWts below 500, low water solubility (< 1 mg/L) and are likely to be highly lipophilic (log Pow >6). Like DIDS, they are diesters, and have similar molecular masses. As such, oral absorption of these substances (and hydrolysis products) is expected to be similar to that predicted for DIDS.

Dermal

According to ECHA guidance, for a compound to penetrate the stratum corneum, it must be sufficiently water soluble i.e. above 1 mg/L (ECHA, 2012a). For substances with a log P > 6, the rate of transfer between the stratum corneum and the epidermis will be slow and uptake into the stratum corneum itself may be limited (ECHA, 2012a). The low water solubility (about 0.095mg/L) and high log Pow (>6.5) of DIDS infer that dermal uptake is likely to be very low/slow. Based on these factors, a value of 10% dermal absorption is proposed.

 

Relevant read-across data:

DIDA and DEHS/DOS are likely to be highly lipophilic (log Pow > 6), and have low water solubility (< 1 mg/L). Dermal absorption of these substances is expected to be similar to that predicted for DIDS.

Inhalation

Based on the low volatility of DIDSi.e.very low vapour pressure (< 0.008 KPa) and high boiling point (380 to 440 °C), the opportunity for exposure by inhalation is likely to be insignificant. Any DIDS reaching the respiratory epithelium may be taken up by micellular solubilisation, because of its highly lipophilic character (log P >6.5) and low water solubility. Pre-absorptive hydrolysis may occur in the lungs, leading to absorption of the hydrolysis products. In the absence of test data to the contrary, a default value of 100% inhalation absorption is appropriate.

Relevant read-across data:

DIDA and DEHS/DOS have very low vapour pressures, and are considered to be low volatility substances. The boiling points of these substances are high (> 200 °C). As such, exposure by inhalation is likely to be low, as with DIDS. Likely high lipophilicity (log Pow >6) and low water solubility means that absorption of these substances is expected to be similar to that predicted for DIDS.

DISTRIBUTION and METABOLISM

As described above, the first step in metabolism following ingestion is extensive hydrolysis by gastrointestinal esterases (especially pancreatic lipase). The likely products are iso-decanol, sebacic acid and isodecyl sebacate. Absorption of these hydrolysis products is likely to be extensive. Absorbed mono-ester will presumably be hydrolysed by esterases in the blood to generate additional isodecanol and sebacic acid which will, in turn, follow the normal metabolic pathways for alcohols and acids. The alcohol will be metabolised to the corresponding fatty acid (iso-decanoic acid). The acids will be further metabolized by β-oxidation. The end products of this process will be utilised for energy via the citric acid cycle or converted to acetoacetate and subsequently to other ketone bodies which can be excreted in the urine. Alternatively, iso-decanol or the acids can undergo conjugation and subsequent urinary excretion (EFSA, 2010).

Inhalation of DIDS is unlikely to occur but any inhaled substance could undergo hydrolysis pre- and/or post-absorption. Once absorbed, the molecules will follow similar metabolic pathways as after gastro-intestinal absorption.

No data are available regarding the distribution of any absorbed intact DIDS. Based on its high MWt, tissue distribution of DIDS is expected to be limited. Since the substance is of low solubility, it will not be able to diffuse through aqueous channels and pores (ECHA, 2012a). Based on its lipophilic character (log P >6.5), intracellular concentrations of DIDS are expected to be higher than extracellular concentrations. As a lipophilic substance, intact DIDS has the hypothetical potential to concentrate in adipose tissue but is much more likely to undergo ester hydrolysis and further metabolism, rather than to accumulate in tissues (ECHA, 2012a).

Relevant read-across data:

Based on the high MWt, low solubility and lipophilic character, and the similar structures of DIDA and DEHS/DOS, distribution and metabolism of these substances is expected to be similar to that predicted for DIDS.

EXCRETION

Absorbed hydrolysis products will undergo further metabolism and be utilised for energy via the citric acid cycle or converted to acetoacetate and subsequently to other ketone bodies which can be excreted in the urine. Alternatively, iso-decanol or the acids can undergo direct conjugation and subsequent urinary excretion (EFSA, 2010). Any absorbed intact DIDS could hypothetically be excreted in the faeces, via the bile, as this tends to involve conjugated substances and those with higher MWts (>300 in the rat, approximately >500 in humans) (ECHA, 2012a; OECD, 2011). However, the extent of this route of excretion is likely to be insignificant because the body has a high capacity for hydrolysing esters to acids and alcohols.

Any substance persisting in the stratum corneum may eventually be cleared as the stratum corneum is sloughed off (ECHA, 2012a).

Relevant read-across data:

Based on the low water solubility, high MWts, and hydrolysis/metabolism/conjugation, excretion of DIDS and its metabolites will be similar to that of DIDA and DEHS/DOS.

 

 

References

EFSA (2010). European Food Safety Authority.Conclusion on pesticide peer review. Conclusion on the peer review of the pesticide risk assessment of the active substance 1-decanol. EFSA Journal 8(9), 1715, 1-42. http://www.efsa.europa.eu/en/efsajournal/doc/1715.pdf

OECD (2011).Organisation for Economic Co-operation and Development.Manual for the assessment of chemicals. Chapter 4. Initial assessment of data. http://www.oecd.org/env/ehs/risk-assessment/49188998.pdf