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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
20
Absorption rate - inhalation (%):
100

Additional information

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 data set.

Absorption

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 mucociliary activity.

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 mg/cm2/event).

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.

Distribution

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.

Bioaccumulation

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 reached.

After dermal exposure, highly lipophilic compounds may persist in the stratum corneum, as systemic absorbance is hindered.

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 continuous exposures.

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.

Metabolism

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 questionable.

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. 

Excretion

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.