Amides, mixed C16-18 and C18-unsatd. branched and linear and tall-oil fatty, N,N'-(iminodi-2,1-ethanediyl)bis-, maleated

Endpoint summary

Description of key information

A theroretical 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, tall-oil, reaction products with fatty acids C16-C18 and C18-unsatd, branched and linear, diethylenetriamine and maleic anhydride is made based on the physical and chemical properties of the substance and the available toxicity studie son the substance and the analogues, Fatty acids, tall-oil, reaction products with diethylenetriamine, maleic anhydride, tetraethylenepentamine and triethylenetetramine (see table under physicochemical properties) and fatty acids, tall-oil, reaction products with diethylenetriamine and maleic anhydride. The properties of the analogues are considered sufficiently similar to those of the test substance to allow read-across (see chapter 13, document on read-across).

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 substance, it can be concluded that the log Kow is high (> 6.5 and potentially much higher (QSAR ca. 11)) and the water solubility is low (<0.2 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 655 to 735 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 substance has a low water solubility, therefore it is expected to dissolve to a small extent into the gastrointestinal fluids. Uptake by passive diffusion is thus limited, but it will occur.

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

(3) The 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 available 90-day study with the analogue, fatty acids, tall-oil, reaction products with diethylenetriamine and maleic anhydride (Charles River 2016), no adverse effects were reported at any of the tested doses (NOAEL 1000 mg/kg bw). This can be either indicative for low systemic availability or for low toxicity. In a developmental toxicity with the same analogue no effects were found related to maternal or developmental toxicity (NOAEL 1000 mg/kg bw, Charles River 2016).

In the repeated dose-reproduction study available on the analogue Fatty acids, tall-oil, reaction products with diethylenetriamine, maleic anhydride, tetraethylenepentamine and triethylenetetramine (BSL 2010c), no systemic effects were found after oral administration. The multifocal bronchopneumonia in the lungs reported in the repeated dose study in rats were attributed to reuptake of part of the stomach contents and as such do not provide evidence for absorption via the oral route.

 

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 Main physicochemical characteristics

Data	Fatty acids, tall-oil, reaction products with fatty acids C16-C18 and C18-unsatd, branched and linear, diethylenetriamine and maleic anhydride	Fatty acids, tall-oil, reaction products with diethylenetriamine, maleic anhydride, tetraethylenepentamine and triethylenetetramine	Fatty acids, tall-oil, reaction products with diethylenetriamine and maleic anhydride
Molecular weight	655-735	>800	735-799
State of the substance at 20°C and 101,3 kPa	paste	Solid (paste)	paste
Melting / freezing point	33°C(pour point)	>500 °C	33°C(pour point)
Boiling point	>184°C(decomposition)	>500 °C	>193°C(decomposition)
Vapour pressure	2.4E-03 Pa	Waiver (melting point > 300 °C)	5.6E-04 Pa
Surface tension	Waiver (WS)	Waiver (solid)	Waiver (WS)
Water solubility	<0.2 mg/L	2.173 mg/L ( undissolved substance present)	<0.2 mg/L
Log Kow	>6.5 (test) ca. 11 QSAR	Waiver (not measurable for UVCB, calculation with Petrorisk)	>6.5 (test) ca. 11 QSAR

 

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 (< 0.2 mg/L), the transfer between the stratum corneum and the epidermis will be limited.

In vitro skin irritation and corrosion studies show that the substance is not irritant and/or corrosive. The available acute dermal toxicity test with the analogue (Ahuia 2010) does not indicate any systemic effects, but showed some very slight irritation. The substance is a skin sensitizer and is therefore expected to have some potential for dermal absorption.

 

The effects in the lungs in the repeated dose study with the analogue are related to the oral exposure route. The other available studies on fatty acids, tall-oil, reaction products with diethylenetriamine and maleic anhydride do not show any systemic effects and can be used for route-route extrapolation.

 

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 (655-735) fulfils the criterion

2) the log P is considerably outside the stated range (> 6.5 (ca. 11)) and

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

 

Inhalation

The low vapour pressure (2.4E-03 Pa) 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. This is confirmed by the results of the repeated dose-reproduction study on the analogue (Rudragowda 2010), where effects in the lungs become apparent when the lungs are exposed to the stomach content. 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. This is in line with the findings in the 90-day study and the developmental toxicity study with fatty acids, tall-oil, reaction products with diethylenetriamine and maleic anhydride(Charles River 2016). The substance has a molecular weight of 655-735Da. 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, 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 absorbed components 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 acyl chain is shortened two carbon atoms at a time. Maleic anhydride may undergo metabolism to the acid and concurrent conjugation.

 

Excretion

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