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EC number: 946-101-1
CAS number: -
were no studies available in which the toxicokinetic properties of the
test substance were investigated. However, as per REACH guidance
document R7. C (ECHA, 2017), information on absorption, distribution,
metabolism and excretion may be deduced from the physicochemical
properties. Based on the physicochemical properties, QSAR
predictions/modelling as well as the available toxicological data, the
test substance is expected to have relatively higher absorption
potential via the oral and inhalation route compared to the dermal
route. It is likely to be metabolised via aliphatic hydroxylation
phase-I reaction. Overall, the substance is expected to have low
on physicochemical properties:
to REACH guidance document R7.C (ECHA, 2017), oral absorption is
maximal for substances with molecular weight below 500.
Water-soluble substances will readily dissolve into the
gastrointestinal fluids; however, absorption of hydrophilic
substances via passive diffusion may be limited by the rate at which
the substance partitions out of the gastrointestinal fluid. Further,
absorption by passive diffusion is higher at moderate log Kow vales
(between -1 and 4). If signs of systemic toxicity are seen after
oral administration (other than those indicative of discomfort or
lack of palatability of the test substance), then absorption has
test substance is a UVCB with mono- and di- phosphate ester
constituents of varying carbon chain length (C16-20), having a
molecular weight (MW) ranging from 275.18 to 869.51 g/mol and an
average MW of 492.3 g/mol.
is a liquid with poor water solubility of 0.008-0.032 mg/L and a
calculated log Kow of >8.53 (based on solubility in octanol and
on the R7.C indicative criteria, oral uptake of the constituents of
the test substance is assessed to be low, given the average
molecular weight exceeding 500, poor water solubility and high log
Kow values of the test substance. This is supported by the absence
of systemic effects in a combined oral repeated dose and
reproductive and development toxicity screening study in rats up to
the highest tested dose.
on QSAR prediction:
intestinal absorption (HIA) can also be predicted for the
constituents of the test substance using the Multicase model v.3.45
of the OECD QSAR Toolbox v.3.4. HIA is expressed as a percentage of
the oral dose absorbed from the gastrointestinal tract. Substances
with HIA values of 80% are considered well absorbed and with 90%
values are extensively and almost completely absorbed. For those
compounds for which the absorption was reported as being poor, the
value is 5%.
estimated HIA of the constituents were found to range from 67.8 to
92.6%, with a weighted average value of 74%. Based on the above
data, the test substance is expected to be moderately absorbed
through the oral route.
on all the available weight of evidence information, the test
substance can be expected to have low to moderate absorption through
the oral route. Therefore, as a conservative approach, a default
value of 50% has been considered for the risk assessment.
to REACH guidance document R7.C (ECHA, 2017), dermal absorption is
maximal for substances having molecular weight below 100 together
with log Kow values ranging between 2 and 3 and a water solubility
in the range of 100-10,000 mg/L. Substances with MW above 500 are
considered to be too large to penetrate skin. Further, dermal uptake
is likely to be low for substances with log P values <0 or <-1, as
they are not likely to be sufficiently lipophilic to cross the
stratum corneum. Similarly, substances with water solubility below 1
mg/L are also likely to have low dermal uptake, as the substances
must be sufficiently soluble in water to partition from the stratum
corneum into the epidermis.
test substance is a liquid, with an average MW weight of 492.3
g/mol, poor water solubility and an experimental log Kow greater
than 4. This suggests that, the test substance will have a low
penetration potential through the skin.
two well-known parameters often used to characterise percutaneous
penetration potential of substances are the dermal permeability
and maximum flux (Jmax). Kp reflects the speed with which a chemical
penetrates across stratum corneum (SC) and Jmax represents the rate
of penetration at steady state of an amount of permeant after
application over a given area of SC. Out of the two, although Kp is
more widely used in percutaneous absorption studies as a measure of
solute penetration into the skin. However, it is an impractical
parameter because for a given solute, the value of Kp depends on the
vehicle used to deliver the solute. Hence, Jmax i.e., the flux
attained at the solubility of the solute in the vehicle is
considered as the more useful parameter to assess dermal penetration
potential as it is vehicle independent (Robert and Walters, 2007).
absence of experimental data, Jmax can be calculated by multiplying
the estimated water solubility with the Kp values from DERMWIN v2.01
application of EPISuite v4.1. The calculated Jmax of the
constituents was found to range from 1.33E-03 μg/cm2/h to 8.62E-10
μg/cm2/h, with a weighted average value of 0.01μg/cm2/h.
the default dermal absorption for substances with Jmax is ≤0.1
μg/cm2/h is less than 10%. Based on these calculations, the test
substance is predicted to be poorly absorbed via the dermal exposure
Based on all the available weight of evidence information, the test
substance can be expected to have a very low absorption through the
dermal route. However, the test substance is a skin sensitizer which
suggests some amount of dermal absorption. Therefore, a value of 10%
has been considered for the risk assessment.
to REACH guidance document R7.C (ECHA, 2017), inhalation absorption
is maximal for substances with VP >25 KPa, particle size (<100 μm),
low water solubility and moderate log Kow values (between -1 and 4).
Very hydrophilic substances may be retained within the mucus and not
available for absorption.
test substance, because of its relatively low vapour pressure of ≤14
Pa 20°C or ≤120 Pa at 50°C (as worst case), will not be available as
vapours for inhalation under ambient conditions. Therefore, the
substance will neither be available for inhalation as vapours nor as
aerosols. Further, if at all there is any inhalation exposure,
considering the poor water solubility of the substance it is not
expected to be retained in the mucus and the majority of the test
substance may reach the lower respiratory tract. The absorption fate
of the deposited material thereafter is expected to be similar to
the oral route/gastrointestinal tract.
if inhaled, based on all the available weight of evidence
information, the test substance can be expected to have moderate
absorption through the inhalation route. Therefore, as a
conservative approach, a default value of 100% has been considered
for the risk assessment.
on identified literature:
transformation study following oral or intraperitoneal administration of
14C-labelled shorter chain trialkyl phosphate ester, tributyl
phosphate (TBP), revealed oxidation as the first stage metabolic
process, catalysed by cytochrome P-450-dependent
mono-oxygenase, at the ω or ω
-1 position on the butyl chains. The hydroxyl groups generated at the ω or ω
-1 position were further oxidized to produce carboxylic acids
and ketones, respectively
(Suzukiet al., 1984a). Following
these oxidations, the oxidized alkyl moieties were removed as
glutathione conjugates, which
were then excreted as N
–acetyl cysteine derivatives in urine (Suzukiet al.,
on QSAR modelling:
above evidence is supported by the predicted metabolism for the test
substance using thein
metabolism and the rat liver S9 metabolism simulators of the OECD
QSAR Toolbox v.3.4.According to both simulators, all the major
constituents (present at >5%) are primarily predicted to undergo
aliphatic hydroxylation atωposition,
as the first metabolic reaction. See below table for the reaction
sites. For further details, refer to the read across justification.
on the MW and physicochemical information (log Kow and water
solubility) and metabolism prediction, the bioaccumulation potential
of the substance is expected to be low.
on the MW and poor water solubility, the urinary excretion of the
test substance as such is expected to be low. Nevertheless,
similar to TBP, there will be urinary excretion of the resultant
water soluble metabolites.
Kp = -2.80 + 0.66 log kow – 0.0056 MW
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