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Toxicokinetic assessment of Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate

 

There are no studies available in which the toxicokinetic behaviour of Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate.

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 Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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).

 

Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate is paste at room temperature and has a molecular weight of 284-428 g/mol and a water solubility of< 0.0025 mg/Lat 20 °C. The log Pow is >6.5 and the vapour pressure was calculated to be 0.0355 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 Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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 Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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).

After oral ingestion Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate is expected to undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes to the respective alcohols as well as acetic acid. 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 micellar solubilisation (ECHA, 2012).

 

The results of oral studies performed with the alcohol hydrolysis products or analogue alcohols are indicative for low toxicity (EC50 > 2000 mg/kg and NOAEL > 1000 mg/kg bw). Acetic acid is corrosive but when formed after hydrolysis is expected to be of little influence on toxicity.

 

Overall, a systemic bioavailability of Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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 Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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 Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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).

The molecular weight of Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate would be in the expected range for good absorption, but the low water solubility, the high log Pow value and the fact that the substance is not irritating to skin imply that dermal uptake is expected to be very limited.

Inhalation:

Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate has a vapour pressure of 0.0355 Pa at 20 °C. The substance is thus of low 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).
Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products hexadecanol, stearyl alcohol, oleyl alcohol and acetic acid.

These smaller alcohol molecules with similar physico-chemical properties as their parent will be mainly distributed into cells and intracellular space and subject to rapid metabolism. Acetic acid 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 the distribution of Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate and its cleavage products will be limited.

 

Metabolism

 

Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate is 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, Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate likewise undergoes stepwise enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, when absorbed through the pulmonary alveolar membrane or through the skin the substance enters the systemic circulation directly before entering the liver where hydrolysis will basically take place.

After hydrolysis, the cleavage products, hexadecanol, stearyl alcohol, oleyl alcohol, are mainly oxidized to the respective acids which are either glucuronidated or to a small extend further oxidized (beta oxidation) leading to various products (ultimately CO2). The other cleavage product, acetic acid, will be metabolized rapidly to CO2.

Overall, hexadecanol, stearyl alcohol, oleyl alcohol is hydrolysed and the cleavage products are metabolized by beta oxidation and/or glucuronidation.

  

Excretion

 

For Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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 Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate 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 Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate is predicted to mirror those of mammalian derived dietary lipids and to utilise the same biochemical pathways and cycles. 

     

 

 


[1]Octadecanol (stearyl alcohol) MW 270, WS < 1 mg/L, logKow 7.4

Oleyl alcohol: MW 268, WS 0.042 mg/L, logKow 7.07

Cetyl alcohol: MW 242, WS <0.11 mg/L, logKow 8.68

Lanolin alcohol: MW 300-500, WS 0.1-0.4mg/L, LogKow > 8

 

 

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