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EC number: 407-560-9
CAS number: 107934-68-9
There are no experimental studies available in which the toxicokinetic behaviour of 4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) has been assessed. Based on the physico-chemical data possible absorption via the oral route may occur due to micellar solubilisation. Dermal absorption is supposed to be rather low (approximately 1%). Inhalation of the test substance as such is supposed to be possible. Aerosol formation may enhance possible absorption via inhalation. If the substance enters the body it may be accumulated in lipid tissues. Excretion is assumed to take place via bile and faeces.
There are no experimental studies
available in which the toxicokinetic behaviour of
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) (CAS 107934-68-9) has
In accordance with Annex VIII, Column
1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on
information requirements and chemical safety assessment Chapter R.7c:
Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic
behaviour of the substance is conducted to the extent that can be
derived from the relevant available information. This comprises a
qualitative assessment of the available substance specific data on
physicochemical and toxicological properties according to the relevant
Guidance (ECHA, 2012).
The substance of
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) is a monoconstituent
substance with a molecular weight of 417.3 g/mol. It is a solid white
powder with a water solubility of < 0.052 mg/L at 20 °C and a vapour
pressure < 0.0001 Pa. Analysis of particle size revealed that 91.7% of
the particles are <100 µm, 4.08% are <10 µm, and 0.312% are < 5.5 µm.
The log Pow was determined to be > 4.49 at 21°C (pH 5.28-5.88) and was
calculated to be 6.49.
Absorption is a function of the
potential for a substance to diffuse across biological membranes. The
most useful parameters to provide information on this potential are the
molecular weight, octanol/water coefficient (log Pow) value and water
solubility (ECHA, 2012). The log Pow value provides information on the
relative solubility of the substance in water and lipids (ECHA, 2012).
The molecular weight of
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) is lower than 500 g/mol,
indicating that the substance is available for absorption (ECHA, 2012).
The high log Pow in combination with the low water solubility suggests
that any absorption will happen via micellar solubilisation (ECHA, 2012).
The available acute oral toxicity data
revealed a LD50 > 5000 mg/kg bw and no systemic effects were observed
(Glaza, 1988a). In a 28-day repeated dose toxicity study no
toxicologically relevant effects were noted up to and including the
highest dose level of 1000 mg/kg bw/day (Edwards, 1991). This indicates
that 4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) has a low potential
for oral toxicity, although no assumptions can be made regarding the
absorption potential based on the experimental data.
The dermal uptake of liquids and
substances in solution is higher than that of dry particulates, since
dry particulates need to dissolve into the surface moisture of the skin
before uptake can begin. Molecular weights below 100 favour dermal
uptake, while for those above 500 the molecule may be too large. Dermal
uptake is anticipated to be low, if the water solubility is < 1 mg/L;
low to moderate if it is between 1-100 mg/L; and moderate to high if it
is between 100-10000 mg/L. Dermal uptake of substances with a water
solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance
may be too hydrophilic to cross the stratum corneum. Log Pow values in
the range of 1 to 4 (values between 2 and 3 are optimal) are favourable
for dermal absorption, in particular if water solubility is high. For
substances with a log Pow 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. Log Pow
values above 6 reduce the uptake into the stratum corneum and decrease
the rate of transfer from the stratum corneum to the epidermis, thus
limiting dermal absorption (ECHA, 2008).
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) is poorly soluble in
water, indicating a low dermal absorption potential (ECHA, 2012). The
molecular weight (417.3 g/mol) indicates that dermal absorption is
possible. The log Pow is > 4.49 (>6.49, QSAR), which means that the
uptake into the stratum corneum is likely to be slow and the rate of
transfer between the stratum corneum and the epidermis will be slow
The dermal permeability coefficient
(Kp) can be calculated from log Pow and molecular weight (MW) applying
the following equation described in US EPA (2004):
log(Kp) = -2.80 + 0.66 log Pow –
The Kp is thus 0.00673 cm/h.
Considering the water solubility (0.052 mg/cm³) the dermal flux is
estimated to be < 1 ng/cm²/h and thus the dermal absorption potential is
estimated to be very low (1% dermal absorption; Kroes at al., 2007).
In addition the substance is not a
skin irritant or corrosive, thus penetration is not supposed to be
enhanced by damage to the skin surface (ECHA, 2012).
Data from an available acute dermal
toxicity data revealed a LD50 > 2000 mg/kg bw and no systemic effects or
other signs of toxicity were observed (Baldrick, 1991). This is in
accordance with the estimated dermal absorption potential, but no direct
conclusion can be drawn from this study regarding toxicokinetic
behaviour, as absence of effects could also be due to chemical
properties and not only toxicokinetic properties.
As the vapour pressure of
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) is very low (< 0.0001 Pa
at 20 °C and < 0.01 Pa at 110 °C), the volatility is also very low.
Therefore, the potential for exposure and subsequent absorption via
inhalation of vapour during normal use and handling is considered to be
negligible. If the substance is available as an aerosol or as dust, the
potential for absorption via the inhalation route is increased. While
droplets and particles with an aerodynamic diameter < 100 μm can be
inhaled, in principle, only droplets and particles with an aerodynamic
diameter < 50 μm can reach the bronchi and droplets and particles < 15
μm may enter the alveolar region of the respiratory tract (ECHA, 2012).
The substance includes particles <10 µm (4.08%) indicating that exposure
of the alveolar region cannot be excluded, but will take place to a
smaller amount, as the bigger part of the substance consists of bigger
particle sizes. As for oral absorption, the molecular weight, log Pow
and water solubility are suggestive of absorption across the respiratory
tract epithelium by micellar solubilisation. In the available acute
inhalation toxicity study a LC50 > 3 mg/L air (maximum attainable
concentration) was derived in rats for
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) (WIL Research Europe
B.V., 2015). Body weight loss was seen for all females during the first
week post-exposure. However, despite one female, the remaining animals
regained weight until the end of the observation period thus exceeding
the initial body weight. Overall body weight gain in males appeared
normal. No clinical signs were noted. This indicates that the test
substance has a low potential for inhalation toxicity, although no
assumptions can be made regarding the absorption potential based on the
experimental data. Absorption via inhalation is in general assumed to be
possible, but will not exceed the oral absorption potential.
Distribution and Accumulation
Distribution of a compound within the
body depends on the physicochemical properties of the substance;
especially the molecular weight, the lipophilic character and the water
solubility. In general, the smaller the molecule, the wider is the
distribution. If the molecule is lipophilic, it is likely to distribute
into cells and the intracellular concentration may be higher than
extracellular concentration, particularly in fatty tissues (ECHA, 2012).
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline) is absorbed systemically
it may be distributed into cells particularly in fatty tissues.
Substances with high log Pow (>4) may accumulate in fatty tissues or as
poorly soluble particulates in the alveolar region.
No experimental data are available for
the characterisation of metabolites of
4,4'-(9H-fluoren-9-ylidene)bis(2-chloroaniline). General metabolism
would include hydroxylation of the amino moiety and/or the aromatic
rings at various positions, as suggested by the OECD toolbox (v3.0). The
metabolites proposed from the rat liver S9 metabolism simulator (OECD
toolbox, 3.0) showed some alerts for DNA binding by OASIS v.1.1/DNA
binding by OECD. As all genotoxicity tests performed with the test
substance were negative and showed no difference between treatments with
or without metabolic activation, it can be concluded that either no
relevant metabolism takes place in vivo or the substance is scarcely
bioavailable and thus not available for metabolism at all.
Based on the molecular weight of the
substance and the possible metabolites as well as the low water
solubility, excretion via bile is assumed. In case of conjugation of the
parent substance or the oxidised metabolites with glucuronic acid,
excretion via the faeces could also occur, as the molecular weight of
the conjugates is > 300 g/mol.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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