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Description of key information

A theoretical assessment has been prepared

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information

A toxicokinetic assessment for Fatty acids, C16-18 and C18-unsatd., branched and linear, reaction products with diethylenetriamine and tall-oil fatty acids, Me maleates has been made based on the physical and chemical properties of the substance and the available toxicity studies. A substance can enter the body via the lungs, the gastrointestinal tract, and the skin. To determine the absorption rate, the different routes need to be assessed individually.

 

The size of the molecule, log Kow and water solubility are important factors in uptake and distribution of chemicals. Based on the data generated for the test substance, it can be concluded that the log Kow is high (ca. 11) and the water solubility is low (ca. 3.2E-08 mg/L mg/L). Most of the components in the test substance are a-polar, due to the large a-polar tails of the incorporated fatty acids. Molecular weights range from 680 to 760 Da.

 

Oral absorption

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration.

(1) The test substance has a very low water solubility, therefore it is expected to dissolve to a small extent into the gastrointestinal fluids. Uptake by passive diffusion is thus limited.

(2) Based on the molecular weight range, absorption is expected to be low.

(3) The test substance has a high log Kow, which makes the compound very hydrophobic. This characteristic will enable micellular solubilisation by bile salts in the gastro-intestinal tract which allows crossing of lipid biomembranes.

 

In the repeated dose-reproduction study available (Harlan 2013g), no systemic effects were found after oral administration.

Based on this finding and the physicochemical properties as discussed above, limited or no absorption of the test substance is anticipated. The oral absorption is therefore set at 10%.

 

Table 1. Main physicochemical characteristics

 

Data Required

Fatty acids, C16-18 and C18-unsatd., branched and linear, reaction products with diethylenetriamine and tall-oil fatty acids, Me maleates 

Molecular weight

680-760

State of the substance at 20°C and 101,3 kPa

extremely viscous liquid

Melting / freezing point

30°C(pour point)

Boiling point

>400 °C

Relative density

1.01

Vapour pressure

2.3E-03 Pa at 25 °C.

Surface tension

Waiver (solid)

Water solubility

2.5-3.2E-08 mg/L (estimation)

Log Kow

11 (estimation)

 

Dermal absorption

When the substance comes in contact with the skin, the first layer of the skin, the stratum corneum, forms a barrier for hydrophilic compounds. The substance has a log Pow > 6, suggesting that the substance can be taken up in the stratum corneum. Due to its low water solubility (3.2E-08 mg/Ll), the transfer between the stratum corneum and the epidermis will be limited.

Anin vitroskin irritation study showed that the substance was moderately irritating to skin, but thein vitrocorrosion study does not report any corrosion, which might enhance dermal absorption significantly. The available acute dermal toxicity test (Harlan 2013d) does not indicate any systemic effects, but the substance is a skin sensitizer. There are indications that the sensitization potential may be slightly enhanced due to the irritant properties of the test substance (Arts et al. 2006).

 

According to the criteria given in the REACH Guidance, 10% dermal absorption will be considered in cases where the MW >500 and log Pow <-1 or >4. The weight of evidence of the following factors indicates that the substance can be assumed to have a dermal absorption of 10%:

1) the molecular weight (680-760) approaches the criterion

2) the log P is considerably outside the stated range (ca. 11) and

3) skin irritation testing did not report any corrosive effects which would enhance absorption significantly.

 

Inhalation

The low vapour pressure (2.3E-03Pa) indicates that the test substance has a very low volatility and is not expected to evaporate and become available via inhalation. Moreover, aerosol formation is not expected from the current uses. Therefore exposure of the respiratory tract is not likely. If, however, the test substance would reach the tracheobronchial region, it is not likely to dissolve within the mucus lining the respiratory tract due to its low water solubility. But based on its high log Kow, micellular solubilisation may occur which could enable some uptake of the substance by crossing of biomembranes.Based on the above data, for risk assessment purposes the inhalation absorption of the substance is set at 10%.

 

Both the oral and the inhalation route are considered not relevant as exposure routes and are therefore not further considered.

 

Bioavailability and metabolism

Once absorbed, wide distribution of the test substance throughout the body is not expected based on its low water solubility. The substance has a molecular weight of680 to 760 Da. In general, molecules of this size do not pass readily through cell membranes thus limiting wide distribution. Based on its size and its low water solubility, distribution is expected to be limited. Based on its high partition coefficient (ca. 11), it might initially be assumed that some test substance will distribute into cells and accumulate in adipose tissue. However, for highly hydrophobic substances, experimental data demonstrate that bioaccumulation factor (BCF) values tend to decrease with increasing log Kow above 6. For the substance therefore no bioaccumulation is expected.

 

Any absorbedcomponents of the test substance are expected to be metabolized to some extent. For the fatty acid tails ß-oxidation is likely to be the major fate in mammals. Fatty acids are oxidized in mitochondria by a sequence of reactions in which the fatty alkyl chain is shortened two carbon atoms at a time. Methyl hydrogen maleate may be hydrolysed with concomitant conjugation and excretion. 

 

Excretion

Excretion of the test substance will be via the faeces either via the bile (high molecular weight) or directly without becoming systemically available.

 

 

Reference

 

Arts et al., Dose-Response Relationships and Threshold Levels in Skin and Respiratory Allergy,Critical Reviews in Toxicology, 36:219–251, 2006