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EC number: 202-936-7
CAS number: 101-37-1
No data on absorption, distribution,
metabolism and excretion of TAC are available.
According to REACH, the human health hazard
assessment shall consider the toxicokinetic profile (Annex I). However,
generation of new data is not required as the assessment of the
toxicokinetic behaviour of the substance should be performed to the
extent that can be derived from the relevant available information
(REACH Annex VIII, 8.8.1).
Qualitative information on toxicokinetic
behaviour can be derived taking into account the information on the
chemical properties of the compound as well as data obtained in a basic
The observation of systemic toxicity
following exposure by any route is an indication for substance
absorption; however, this will not provide any quantitative information.
Since acute oral toxicity was observed with TAC, absorption of the
compound via the gastrointestinal tract (at least to some extent) has
evidently occurred. The lack of dermal acute toxicity does not per se
demonstrate a lack of dermal uptake. However, the toxic effects
demonstrated after oral exposure were not observed after dermal
exposure; this lack of dermal toxicity is presumably due to low or no
dermal uptake in contrast to oral absorption. No information on
inhalatory toxicity is available; but as the data available demonstrate
the potential for absorption after oral exposure the substance is likely
to be also absorbed if inhaled.
To be absorbed, the substance has to cross
biological membranes, either by active transport mechanisms or - as
being the case for most compounds - by passive diffusion. The latter is
dependent on compound properties such as molecular weight,
lipophilicity, or water solubility. In general, low molecular weight (MW
≤ 500) and moderate lipophilicity (log P values of -1 to +4) are
favourable for membrane penetration and thus absorption. The molecular
weight of TAC is relatively low with 249.27, favouring oral absorption
of the compound. Dermal uptake can be seen to be moderate at this
molecular weight level (<100: dermal uptake high; >500: no dermal
uptake). This is supported by the determined log P value being 3.51,
being advantageous for oral, respiratory and dermal absorption. In
addition, the moderate water solubility of 0.3 g/L leading to a ready
dissolving of the compound in the gastrointestinal fluids favours oral
absorption. Also for dermal uptake, sufficient water solubility is
needed for the partitioning from the stratum corneum into the epidermis.
In the respiratory tract, the compound would readily diffuse into in the
mucus lining. However, very hydrophilic substances might be retained in
the mucus in the upper respiratory tract and transported out by
According to QSAR predictions obtained from
the Danish (Q)SAR database (2009), gastrointestinal absorption is
presumed to be 100%, whereas dermal uptake is predicted to be low (0.001
Rarely, exogenous compounds (e. g. similar to
a nutrient) may be taken up via a carrier mediated or active transport
mechanism. However, prediction in this direction is not generally
possible. Active transport (efflux) mechanisms also exist to remove
exogenous substances from gastrointestinal epithelial cells thereby
limiting entry into the systemic circulation. From physicochemical data,
identification of substances ready for efflux is not possible.
Some information or indication on the
distribution of the compound in the body might be derived from the
available physico-chemical and toxicological data. Once a substance has
entered the systemic circulation, its distribution pattern is likely to
be similar for all administration routes. However, first pass effects
after oral exposure influence the distribution pattern and distribution
of metabolites is presumably different to that of the parent compound.
The smaller a molecule, the wider is its
distribution throughout the body. In general, membrane-crossing
substances with a moderate log P and molecular weight will be able to
cross the blood- brain and blood-testes barrier and reach the central
nervous system (CNS) or testes, respectively. However, due to the high
water solubility, penetration of TAC through these barriers is
presumably limited. Nevertheless, from the toxicological studies, the
predominant target organs after repeated exposure to TAC were identified
to be the central nervous system (CNS) and the liver. Thus, distribution
throughout the body – at least to some extend – can be presumed. The CNS
effect detected gives strong evidence for penetration of TAC through the
blood-brain barrier. No effects on spermatogenesis were observed, thus
no conclusion regarding blood-testes barrier penetration can be drawn.
Although there is no direct correlation
between the lipophilicity of a substance and its biological half-life,
highly lipophilic (log P > 4) compounds tend to have longer half-lives.
Thus, they potentially accumulate within the body in adipose tissue,
especially after frequent exposure (e. g. at daily work) and the body
burden can be maintained for long periods of time. After the stop of
exposure, the substance will be gradually eliminated dependent on its
half-life. During mobilization of fat reserves, e. g. under stress,
during fasting or lactation, release of the substance into the serum or
breast milk is likely, where suddenly high substance levels may be
After dermal exposure, highly lipophilic
compounds may persist in the stratum corneum, as systemic absorbance is
Substances with log P values of ≤ 3 would be
unlikely to accumulate with the repeated intermittent exposure patterns
normally encountered in the workplace but may accumulate during
With the log P value of 3.51, TAC is
moderately lipophilic and thus unlikely to accumulate in adipose tissue
during 8h-working day scenarios.
Prediction of compound metabolism based on
physico-chemical data is very difficult. Structure information gives
some but no certain clue on reactions occurring in vivo. It is even more
difficult to predict the extent of metabolism along different pathways
and species differences possibly existing.
Evidence for differences in toxic potencies
due to metabolic changes can be derived for instance from in vitro
genotoxicity tests conducted with or without metabolic activation.
Regarding the in vitro genotoxicity of TAC,
some chromosomal aberration studies revealed a positive outcome with
metabolic activation only, which could be interpreted as a hint on some
toxification effect. However, positive results were obtained at special
experimental set-ups and at precipitating or cytotoxic dose levels.
Thus, the relevance of the positive test outcomes is strongly
Expectable enzymatic reactions are
epoxidation of the double bonds, hydrolysis as well as ether cleavage.
Formation of metabolites such as acrylic acid, propanoic acid or
acrolein is possible. In addition phase I oxidation products may be
conjugated by phase II enzymes.
Only limited conclusions on excretion of a
compound can be drawn based on physico-chemical data. Due to metabolic
changes, the finally excreted compound may have few or none of the
physico-chemical properties of the parent compound. In addition,
conjugation of the substance may lead to very different molecular
weights of the final product.
Since no information regarding the metabolism
of TAC is available, no prediction of excretion routes is possible.
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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