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SCAE Methyl Esters (SCAE Me esters) ¿ Assessment of the Toxicokinetic Behaviour

  

SCAE Me esters category members include:

 

Hexanoic acid, methyl ester (CAS No.):106-70-7 ¿ (MW 130.19).

Octanoic acid, methyl ester (CAS No.):111-11-5 ¿ (MW 158.24).

Decanoic acid, methyl ester (CAS No.):110-42-9 ¿ (MW 186.29).

Dodecanoic acid, methyl ester (CAS No.):111-82-0 (MW 214.35).

 Tetradecanoic acid, methyl ester (CAS No.):124-10-7 (MW 242.40).

Hexadcanoic acid, methyl ester (CAS No.): 112-39-0 ¿ (MW 270.46).

Octadecanoic acid, methyl ester (CAS No.):112-61-8 (MW 298.51).

9,12-Octadecadienoic acid (Z,Z)-, methyl ester (CAS No.):112-63-0 (MW 294.48).

9-Octadecenoic acid (Z)-, methyl ester (CAS No.):112-62-9 (MW 294.48).

Fatty acids, C8-10, methyl esters (CAS No.):85566-26-3 ¿ (MW 158.24-186.29).

Fatty acids, C10-16, methyl esters (CAS No.):67762-40-7- (MW 186.29-270.46).

Fatty acids, C6-10, methyl esters (CAS No.): 68937-83-7- (MW 186.29 ¿ 270.46).

Fatty acids, C8-18 and C18-unsatd., methyl ester (CAS No.):67762-37-2- (MW 158.24-298.51).

Fatty acids, C12-18, methyl esters (CAS No.):68937-84-8- (MW 214.35-298.51).

Fatty acids, C16-18, methyl esters (CAS No.): 85586-21-6- (MW 270.46-298.51).

Fatty acids, palm-oil, methyl esters (CAS No.):91051-34-2- (MW 242.40-298.51).

Fatty acids, C16-18 and C18-unsatd, methyl esters (CAS No.):67762-38-3- (MW -270.46-298.51).

Fatty acids, C14-18 and C16-18-unsatd., methyl esters (CAS No.): 67762-26-9 (MW 130.19¿ 290.51).

They are all short chain alkyl fatty acid methyl esters. They are all liquid except Fatty acids, C16-18, methyl esters (CAS No:85586-21-6),Hexadcanoic acid, methyl ester (CAS No: 112-39-0) and Octadecanoic acid, methyl ester (CAS No: 112-61-8) which are waxy solids.

Grouping of the fatty acid methyl esters is justified as they are all metabolised to physiological metabolites (fatty acids) and to a methanol component.

 

SCAE Me esters are all poorly water soluble (<1 mg/L) and have a small molecular weight (130.19-298.51).

 

The logPow of 2.34 to 8.35 indicates that the substances are highly lipophilic and may have the ability to pass through biological membranes.

 

 

Absorption

 

The acute oral toxicity of methyl hexanoate (CAS No. 106-70-7), the category member with the smallest molecular weight of 130.19, was tested in male and female rats. Application of oral doses of 2000 mg/kg bw did not induce any clinical signs of systemic toxicity (Pittermann, 1992). This suggests that the SCAE Me esters are either of low toxicity or there is little absorption of the substance following oral ingestion. Additionally, the read-across substance dodecanoic acid, methyl ester (CAS NO.111-82-0) was tested in a Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test on rats which showed no signs of toxicity after repeated application of 1000 mg/kg bw for 45 days (JECDB, 2000).

 

The moderate logPow values of the some SCAE Me esters category members (between 2 and 4) suggests that they are favourable for absorption by passive diffusion through the gastrointestinal tract. It is also possible that absorption through the gastrointestinal tract could occur by micelullar solubilisation, as this mechanism is of importance for highly lipophilic substances, particulary those who are poorly soluble in water (1 mg/L or less). Therefore absorption through the gastrointestinal tract by micellular solubilisation of some of the SCAE Me esters is a possibility, especially the SCAE Me esters category members with logPow of greater 4 to 8 and water solubility of less than 1 mg/L.

 

QSAR based dermal permeability regarding molecular weight, logPow and water solubility, calculated a dermal absorption of 0.0326 ¿ 3.82 cm/ h (DERMWIN v2.00, 2009) for the SCAE Me esters category members. This value is considered as an indicator that the substances in the SCAE Me esters category have low potential for dermal absorption.

 

LogPow values between 2 and 4 of some of the SCAE Me ester category members favours dermal absorption, however the low water solubility suggest that dermal absorption will be low.

 

For the SCAE Me esters category members with logPow 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 logPow 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 Me esters 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 logPow value suggests that dermal uptake of SCAE Me esters in humans is considered as very limited and the dermal exposition is considered negligible for hazard assessment.

 

SCAE Me esters category members all have low vapour pressure of ¿ 0.5 kPa at 25°C (Kintrup, 2010); therefore indicating that inhalation as a vapour will be minimal. Also, Fatty acids, C16-18, methyl esters(CAS No:85586-21-6), Hexadecanoic acid, methyl ester (CAS No: 112-39-0) and Octadecanoic acid, methyl ester (CAS No: 112-61-8) are all 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 logPow values have long biological half-lives. The high logPow of 6 to 8 of some of the substances indicates that some SCAE Me esters may have the potential to accumulate in adipose tissue.

 

Metabolism

 

Upon systemic uptake, fatty acid methyl esters are readily hydrolysed to the corresponding alcohol (methanol) and fatty 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 (see figure in IUCLID section 7.1.1)

 

Methanol is polar/hydrophilic (log P < -0.5) and thus distributed in the aqueous compartments of the organism. However, direct urinary excretion is known to be low (<3% in humans); unchanged methanol is excreted to some extent via exhalation.

Predominating is the metabolism of methanol: initially, methanol is slowly oxidized by the enzyme alcohol dehydrogenase (ADH) to formaldehyde, which itself is oxidized very rapidly by the aldehyde dehydrogenase (ALDH) to formic acid. Finally, formic acid is slowly metabolised to CO2and H2O (see figure in IUCLID section 7.1.1). These are excreted via exhalation and urinary excretion as predominant excretion way; urinary excretion of formaldehyde and formic acid is possible to a low extent.

Toxicity of methanol is characterised by central nervous effects (drowsiness, ataxia, etc¿), ocular injury and metabolic acidosis. The latter is caused by the accumulation of formic acid due to a relatively slow reaction of the last metabolism step.

Ingestion or inhalation of the fatty acid methyl ester leads to a slow formation of systemic methanol by lipases or esterases. The maximum plasma levels (Cmax) of methanol resulting from systemic hydrolysis of fatty acid methyl esters are expected to be much lower than after ingestion of methanol. The Cmax is the relevant factor that determines the rate of the critical metabolite of methanol, formic acid.

However, studies on acute and repeated dose toxicity of SCAE category members did not result in any signs of systemic toxicity. Furthermore, studies on genotoxicity (Ames-Test, chromosome aberration in vitro, gene mutation in mammalian cells in-vitro) were negative, i.e. there is no indication of a reactivity of SCAE Me esters or its metabolites.

 

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 faeces.

Exemplarily, experimental data of Ethyl Oleate (CAS No. 111-62-6, ethyl ester of oleic acid) provided this assumption: 14C labelled carbon of 5 mL/kg of Ethyl Oleate was rapidly excreted in respiration CO2 (approximately 70%), faeces (7 -10 %), and urine (1-2 %), with essentially complete elimination by 72 hours after administration as demonstrated by Bookstaff et al (Regul Toxicol Pharm 37, 133-148(2003)).