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EC number: 806-509-1
CAS number: 1393571-42-0
A theoretical assessment has been prepared
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.
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
(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
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
Fatty acids, C16-18 and C18-unsatd., branched and linear, reaction products with diethylenetriamine and tall-oil fatty acids, Me maleates
State of the substance at 20°C and 101,3 kPa
extremely viscous liquid
Melting / freezing point
2.3E-03 Pa at 25 °C.
2.5-3.2E-08 mg/L (estimation)
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
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
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.
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 of the test substance will be
via the faeces either via the bile (high molecular weight) or directly
without becoming systemically available.
Arts et al., Dose-Response
Relationships and Threshold Levels in Skin and Respiratory
Allergy,Critical Reviews in Toxicology, 36:219–251, 2006
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