Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid

Endpoint summary

Description of key information

Toxicokinetic Assessment of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid

 

There are no studies available in which the toxicokinetic behaviour of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid has been investigated.

Therefore, 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, 2012), assessment of the toxicokinetic behaviour of the substance Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid 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, 2012).

 

Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is liquid at room temperature and has a molecular weight of 384-496 g/mol and a water solubility of<0.16 mg/L (LOQ)at 20 °C. The log Pow is >6.5 and the vapour pressure was measured to be 143 Pa.

 

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:

In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of the components of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is <500 g/mol, absorption of the molecules in the gastrointestinal tract is in general anticipated.

The log Pow of > 6.5 suggests that the components of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid are favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less).

The results of acute oral studies performed with the analogue substances, Bis(2-ethylhexyl) azelate and Diisodecyl azelate, did not reveal any adverse clinical signs at 2000 mg/kg bw. This indicates that it is predicted that Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is of low toxicity and/or badly absorbed after oral administration.

After oral ingestion Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is expected to undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes. The respective alcohols as well as nonanedioic acid is formed. The physico-chemical characteristics of the cleavage products are likely to 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 the cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract based on their physico-chemical properties[1]by dissolution into the gastrointestinal fluids (ECHA, 2012).

Overall, a systemic bioavailability of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal:

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As the molecular weight of the components of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is <500 g/mol, dermal absorption of the molecule cannot be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is not skin irritating, enhanced penetration of the substance due to local skin damage can be excluded.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is less than 1 mg/L, dermal uptake is likely to be (very) low.

Overall, the low water solubility, the molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is considered as very limited.

Inhalation:

Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid has a vapour pressure of 143 Pa at 20 °C. The substance is not considered to be of high volatility and under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour or gas is considered negligible.

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). When the substance would reach the alveoli, uptake of this lipophilic compound components with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) is expected to be low.

 

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).
Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products 2-ethylhexan-1-ol, Alcohols, C7-9-iso-, C8-rich and azelaic acid (Nonanedioic acid). These small molecules with moderate water solubility and logPow values will be mainly distributed in aqueous compartments of the organism and may also be taken up by different tissues.

Overall, the available information indicates that Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid and its cleavage products will be widely distributed within the organism.

 

Metabolism

 

Dicarboxylic acid esters like Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid are expected have the same metabolic fate as fatty acid esters. Esters of fatty acids are hydrolysed to the corresponding alcohol and carboxylic acid by esterases. Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and dicarboxylic acids likewise undergo stepwise enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances that 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.

In the first step of hydrolysis, the monoester is produced that is further hydrolysed to the alcohol and the dicarboxylic acid. The cleavage products, 2-ethylhexanol and Alcohols, C7-9-iso-, C8-rich, are mainly oxidized to the respective acids which is either glucuronidated or to a small extend further oxidized leading to various products. The other cleavage product, azelaic acid, is partly metabolized by beta-oxidation and is thus incorporated into fatty acid biosynthesis and the citric acid cycle (HSDB, 2011).

Overall, Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is hydrolyzed and the cleavage products are metabolized by beta oxidation and/or glucuronidation.

 

Excretion

 

For Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid and its cleavage products, the main routes of excretion are expected to be via expired air as CO2 after metabolic degradation (beta oxidation) and by renal excretion via the urine.     

 

Conclusion

 

After oral exposure the components of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid are hydrolysed by esterases in the gastro-intestinal tract or the liver. The cleavage products are taken up distributed and metabolised via beta oxidation. Thereafter excretion is mainly via urine.

Uptake via the skin and lungs is limited by the physico-chemical properties of the substance.

No bioaccumulation is expected.

In conclusion the human dermal, oral and inhalation absorption, and subsequent human metabolism, distribution and elimination profile of Diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is predicted to mirror those of mammalian derived dietary lipids and to utilise the same biochemical pathways and cycles.

     

[1]2-ethylhexan-1-ol: MW 130; WS 900 mg/L; LogKow 2.9 (ECHA website)

Alcohols, C7-9-iso-, C8-rich: MW 143-171; WS 75 mg/L; LogKow 3.8 (ECHA website)

Azelaic acid /Nonanedioic acid: MW 188; WS 2400 mg/L; LogPow 1.57 (Pubchem)

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10