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Description of key information

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Toxicokinetic assessment

of the category

Short Chain Fatty Acid Ethyl-, Isopropyl-, Butyl- and 2-Ethylhexyl-Esters

(SCAE C2-C8)

 

The category includes the following members:

 

Ethyl linoleate: CAS No: 544-35-4 (MW 308.50).

Ethyl oleate: CAS No: 111-62-6 (MW 310.51).

Fatty acids, essential, ethyl esters: CAS No: 91051-05-7 (MW 256.43-368.64).

 

Isopropyl laurate: CAS No: 10233-13-3 (MW – 242.40).

Isopropyl myristate: CAS No: 110-27-0 (MW – 270.46).

Isopropyl palmitate: CAS No: 142-91-6 (MW – 298.51).

Isopropyl oleate: CAS No: 112-11-8 (MW – 324.55).

 

Fatty acids, tall-oil, butyl esters: CAS No: 67762-63-4 (MW 336.56-338.57).

Butyl stearate: CAS No: 123-95-5 (MW 340.59).

Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl esters: CAS No: 163961-32-8 (MW 312.54-340.60)

 

2-ethylhexyl oleate: CAS No: 26399-02-0 (MW 394.68).

Fatty acids, C8-16, 2-ethylhexyl esters: CAS No: 135800-37-2 (MW 256.43-312.54).

Fatty acids, C16-18, 2-ethylhexyl esters: CAS No: 91031-48-0 (MW 368.64-396.70).

Fatty acids, C16-18 and C18-unsatd., 2-ethylhexyl esters: CAS No: 85049-37-2 (MW – 368.64-396.70).

2-ethylhexyl palmitate: CAS No: 29806-73-3 (MW 368.64)

 

This category comprises of ethyl, iso-propyl, butyl and 2-ethylhexyl esters. Altogether, the number of carbon atoms varies between 15 (isopropyl dodecanoate, CAS NO. 10233-13-3) and 26 (ethylhexyl octadecenoate, CAS NO. 26399-02-0; this substance or its hydrogenated analogue ethylhexyl octadecanoate are also present in two multi-constituent chemicals: CAS NO. 91031-48-0 and 85049-37-2).

Grouping of these short chain alkyl esters are justified as they are all metabolised to physiological metabolites (fatty acids) and to their respective alcohol component.

 

All SCAE C2-C8 category members are liquids except for butyl stearate (CAS No: 123-95-5) which is a waxy or oily solid.  SCAE C2-C8 are all poorly water soluble (<1 mg/L) and have a small molecular weight (242.40-396.70).

 

The log Pow of 5 to 11 indicates that the substances are highly lipophilic and may have the ability to pass through biological membranes and some of the category members with very high log Pow may even have the ability to accumulate in the body.

 

Absorption

 

All available studies of all category members on the acute oral toxicity resulted in acute oral LD50 > 2000 mg/kg bw in rodents. This suggests that the SCAE C2-C8 members are either of low toxicity or there is little absorption of the substances following oral ingestion. It is possible that absorption through the gastrointestinal tract could occur by micecullar solubilisation, as this mechanism is of importance for highly lipophilic substances, particularly those who are poorly soluble in water (1mg/L or less). The rate at which SCAE C2-C8 molecules diffuse across membranes could limit their distribution.

QSAR based dermal permeability regarding molecular weight, log Pow and water solubility, calculated a dermal absorption of 0.892 – 39.9 cm/ h (DERMWIN v2.00, 2009) for the SCAE C2-C8 category members. This value is considered as an indicator that the substances in the SCAE C2-C8 category have low potential for dermal absorption.

For the SCAE C2-C8 category members with 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. And those with 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. Uptake into the stratum corneum itself may be slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis.

 

Therefore the water solubility of less than 1 mg/L for the SCAE C2-C8 suggests that dermal uptake is likely to be low. Overall the calculated low dermal absorption potential, low water solubility, high molecular weight (>100) and the high log Pow value suggests that dermal uptake of SCAE C2-C8 in humans is considered as very limited and the dermal exposition is considered negligible for hazard assessment.

 

SCAE C2-C8 category members all have low vapour pressure of ≤ 0.357 Pa at 25°C (QSAR); therefore indicating that inhalation as a vapour will be minimal. Also, butyl stearate: (CAS No: 123-95-5) is a waxy solid, therefore the particles paste together and thus the risk of forming respirable dust is minimal. 

  

Highly lipophilic substances will 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. The high log Pow of 6 to 11 of some of the substances indicates that some SCAE C2-C8 may have the potential to accumulate in adipose tissue.

 

 

Metabolism

 

The Fatty Acid SCAE Et-, Bu, Prop- and EtHe esters (SCAE C2-C8) are likely to be metabolised like any other dietary fats. High molecular weight aliphatic esters are readily hydrolysed to the corresponding alcohol and acid and then generally oxidised to carbon dioxide and water via well known metabolism of breakdown into two-carbon fragments which are used by the body for energy and building blocks for synthesis. During digestion, they are hydrolysed to the free fatty acids for absorption from the intestine into the blood stream aided by lipase enzymes and bile salts as demonstrated in the rat by Mattson et al. (IUCLID section 7.1.1, Mattson and Volpenhain, 1972). Once formed the free fatty acid is metabolised by known oxidative processes or they are reconstituted into glyceride esters and stored in the fat depots in the body.

The liver will be the primary site of metabolism of ethanol, butanol, isopropanol and ethylhexanol, where it will undergo phase I and phase II metabolism. Through a series of oxidative steps the alcohols will be oxidised to the corresponding aldehyde and acid and finally detoxified to carbon dioxide. 

Studies on genotoxicity (Ames-Test, gene mutation in mammalian cells in-vitro, cytogenicity tests in vitro and micronucleus assay in-vivo) were negative, i.e. there is no indication of a reactivity of SCAE C2-C8 or its metabolites under the test conditions.

  

 

Excretion

 

The main route of excretion is expected to by expired air as CO2. The second route of excretion is expected to be by biliary excretion and the feces.

Exemplarily, experimental data of ethyl oleate (is the ethyl ester of oleic acid) provided this assumption: 14C-labeled carbon of 5 mL/kg of ethyl oleate (CAS No. 111-62-6) was rapidly excreted in respiration CO2 (approximately 70%), faeces (7 -10%), and urine (1-2%), with essentially complete elimination by 72 hours after administration (IUCLID section 7.1.1, Bookstaff, 2003).