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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
assumption of toxicokinetic
Type of information:
other: assumption of toxicokinetic
Adequacy of study:
supporting study
Reliability:
other: assumption of toxicokinetic
Rationale for reliability incl. deficiencies:
other: assumption of toxicokinetic
Principles of method if other than guideline:
Assumption of toxicokinetics.
GLP compliance:
no

There are no study data available for the toxicokinetic of the test substance TBBS. However, considering the experiences with TBBS in acute and repeated dose toxicity studies, a characterization of TBBS toxicokinetics can be conducted as discussed in the OECD SIDS 2003:

"The test material is a solid. No details of particle size distribution have been given, but a repeated-dose toxicity study using the inhalation route indicates some systemic toxicity. The vapour pressure value for the test material is low (< 0.21 x 10-5 hPa at 25 °C, OECD SIDS 2003).

The test material is expected to hydrolyse readily at pH values below 9. This suggests that systemic exposure to degradants can be expected, particularly following oral ingestion. The log oil/water partition coefficient value is moderate (log Pow 3.9 at room temperature), which suggests that test material passage across biological membranes is possible.

Absorption

The results of the acute and repeated dose oral toxicity studies in the rat suggest that the test material is absorbed from the gastro-intestinal tract. Systemic effects are observed, particularly with cumulative exposure. Because of the rapid hydrolysis of the test material, it is likely that toxicity is a result of exposure to degradants. The test material has low water solubility (0.345 mg/l at 20°C, OECD SIDS 2003) which may restrict absorption of the parent molecule but hydrolysis may enhance water solubility. The moderate log oil/water partition coefficient of the parent molecule will allow passage across the biological membranes of the gastro-intestinal tract. The results of the acute dermal toxicity studies in the rabbit show that the test material is not more toxic by this route. The results of human patch tests and a sensitisation study in the guinea pig show that the test material (or a product of hydrolysis, mercaptobenzothiazole) is absorbed through the skin. The results of a repeat dose study in the rat by inhalation exposure shows that the test material (or a hydrolysis product) can be absorbed by inhalation.

Distribution

The results of the repeat dose oral and inhalation studies in the rat suggest some systemic distribution. Following oral ingestion it is likely that the test material (or hydrolysis products) is distributed via the porta circulation system. The positive sensitisation response suggests that the hydrolysis products may bind to circulatory proteins. The moderate log oil/water partition coefficient value suggests that the test material could potentially accumulate in body fat. Because the test material hydrolyses, it is likely to result in products with a lower partition coefficient value.

Metabolism

The widespread distribution throughout tissues such as the gastro-intestinal tract, and the tendency of the test material to undergo hydrolysis suggest that initial metabolism of the material will be widespread and non-specific. The results of the repeat dose oral and inhalation studies in the rat do show microscopic changes in the liver. This may be indicative of further metabolism of hydrolysis products. The results of in vitro mammalian cell genotoxicity studies show that a positive genotoxic effect is seen, but only in the presence of S9 metabolising system. This indicates that metabolism of the parent test material or a hydrolysis product is required to produce a positive response. The results of separate reproduction/developmental toxicity studies in the rat with the test material and an analogue (either N-cyclohexylbenzothiazole-2-sulfenamide or N, N-dicyclohexylbenzothiazole-2-sulfenamide) show differences in developmental toxicity. If, as expected, the analogues undergo hydrolysis/metabolism as does the test material, it may be suggested that the profile of the metabolites may be significant in the toxicity of the product.

Excretion

The results of some of the repeated dose oral toxicity studies show changes in the kidneys of rats. This suggests that urinary excretion is a significant route for removal of test material" (OECD SIDS 2003).

Executive summary:

Assumption of toxicokinetic

Description of key information

Experimental Data


There are no study data available for the toxicokinetic of the test substance TBBS. However, considering the experiences with TBBS in acute and repeated dose toxicity studies, a characterization of TBBS toxicokinetics can be conducted as discussed in the OECD SIDS 2003:


 


TBBS is a solid. No details of particle size distribution have been given, but a repeated-dose toxicity study using the inhalation route indicates some systemic toxicity. The vapour pressure value for the test material is low (< 0.21 x 10-5hPa at 25 °C, OECD SIDS 2003).


 


TBBS is expected to hydrolyse readily at pH values below 9. This suggests that systemic exposure to degradants can be expected, particularly following oral ingestion. The log oil/water partition coefficient value is moderate (log P 3.9 at room temperature), which suggests that test material passage across biological membranes is possible.


 


ADME Profile


 


Absorption - Oral/G.I.


The structure of TBBS contains several functional groups which may lead to electrophilic/nucleophilic attack which could lead to the evolution of ionizable groups. However due to the sulphane bonding between the benzothizole moiety and the other secondary amine moieties in TBBS, there is a stabilizing effect which will diminish the likelihood of these interactions as opposed to for example BT. Therefore, for the parent substance, ionisation is unlikely to affect absorption.


TBBS is likely readily absorbed due to the molecular weight being below 500 (TBBS MW is 238.4). TBBS is hydrolysed and has a half-life of 7.76 – 9.53 hours and due to the rapid hydrolysis of TBBS, it is likely that toxicity is a result of exposure to degradants. However, the absorption and behaviour of the parent compound can still play a significant role in the toxicokinetics of the substance as it will still remains at 50 % or greater for several hours. Hence, there is time for absorption, distribution, metabolism and possibly excretion prior to full hydrolysis of the substance.


The particle size distribution of TBBS was determined and the median diameter was 91 µm with the main fraction of 70 % distributing in the range of 10 to 100 µm (Karbach, 2010); and hence the tested TBBS particles with sieved size smaller than 100 µm are mainly dominated by inhalable fraction as defined in EN 481/ISO 7708 (1995). The partition coefficient of 3.36 of the parent molecule will allow passage across the biological membranes of the gastro-intestinal tract. TBBS has low water solubility (0.345 mg/L at 20°C, OECD SIDS 2003) which may restrict absorption of the parent molecule, but hydrolysis may lead to water soluble transformation products that may be readily absorbed. In a repeat dose and acute oral toxicity study in the rat, using corn oil as a vehicle the substance was readily absorbed. This is despite the possibility that corn oil may slow absorption, not an impact seen here. The results of the acute oral toxicity (Monsanto, 1973) and repeated dose oral toxicity (Monsanto, 1985) studies performed in the rat, suggest that TBBS is absorbed from the gastro-intestinal tract. In particular systemic effects observed during repeat exposure via the oral route support the absorption of the parent or metabolite (see Table 8, for all toxicological responses and studies).


 


Absorption – Respiratory/inhalation


The vapour pressure for TBBS was determined to be < 0.00021 Pa (Safepharm, 2002) meaning the inhalation route, when the substance is solved, may be of concern (ECHA R.7a, 2017). But is considered to have low vapur pressure as it concerns significant absorption (ECHA R7.c, 2017). TBBS is decomposed at 207 °C meaning vapours exposure is unlikely. The particle size is 70 % in the range of 10-100 µm which means that TBBS does have the ability to be inhaled and potentially reach the thoracic and alveolar regions in humans (ISO 7708:1995, 2017). TBBS may have the potential to be absorbed in the lower respiratory tract, including the alveolar region. TBBS is poorly soluble thus this mucus will limit the amount of the substance that can be absorbed directly. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed (Schlesinger, 1995). It may be that considering the size that the particles reach the tracheo-bronchial region and would mainly be cleared from the lungs by the mucociliary mechanism and swallowed. However, a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system. A fraction of the particle below 15 µm may reach the alveolar region where they would be mainly be engulfed by alveolar macrophages and either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. The subacute inhalation toxicity of TBBS was examined in a subacute inhalation study (Monsanto, 1981). The study is limited concerning the recommended particle-size distribution given as aerosols with mass median aerodynamic diameters (MMAD) ranging from 1 to 3 µm are recommended. The MMAD used in this study was above the recommendations given (8.4 µm) in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biological relevance of sporadic findings reported, especially systemic effects are questionable due to a lack of monotonic dose dependence with effects. The local effects noted in the inhalation study will be used as supporting evidence, where nasal irritation was present. Alopecia was seen in two rats at the highest dose group and urogenital discharge was also noted in several rats at the highest dose group. There were also some noted effects in lymphatic tissues, suggesting that some particles had reached this target. Moreover, increase in aspartate aminotransferase indicate distribution to the liver (i.e. after absorption). These effects (as well as others) would suggest some systemic availability and excretion. Since signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding and thus, no relevant local effects were observed up to 0.084 mg/l. 


 


Absorption - Dermal


In particulate form TBBS is likely to be absorbed to a lesser degree than when dissolved. The molecular weight is between 100 to 500 Da, so based on molecule size only moderate absorption might be expected.  As discussed though some ionisable groups are present on the parent compound, these are unlikely to ionise due to the stabilising effects of the chemical structure and stearic hinderance. So, no slowing of uptake due to this is expected. The water solubility (1.74 mg/L) also suggests low to moderate absorption by the epidermis with a log P that suggests favourable absorption (log P value is between 3-4). Surface tension is not a desired property and the vapour pressure is low, increasing contact time with the skin should exposure be present. There are no trace elements in TBBS. TBBS was more readily taken up when wetted than the dry substance, which is aligns with the above noted expectations (Monsanto, 1973 and Monsanto, 1981). The acute dermal toxicity of TBBS was evaluated in an acute dermal toxicity study with New Zealand albino rabbits (Monsanto 1973). No mortality occurred. The dermal LD50 for the test substance TBBS was greater than 7940 mg/kg bw. The subacute study only showed local and sensitising effects. The vehicles appeared to have little impact on absorption as despite the use of corn oil in the acute study, no further reactions in physiological saline were seen during the subacute study. The results of the acute toxicity and the subacute dermal toxicity studies in the rabbit show that the test material is not toxic systemically by this route. The skin sensitisation results of human patch tests (Monsanto, 1983) and a guinea pig maximisation test (Monsanto, 1982) show that the test material (or a product of hydrolysis, MBT) is absorbed through the skin, leading to skin sensitisation. TBBS breaks down into MBT which leads to skin sensitisation effects by reaction with skin protein molecules, via nucleophilic substitution (SN2) to form disulphide bridge between skin proteins and the benzothiazole moiety, as observed in papers by American Chemistry Council (2003) and Adams (2006).


 


Distribution


The small molecular size of TBBS means that wide distribution is possible. The TBBS log P value is > 0 and therefore it is likely to distribute into cells and the concentration has the potential to be higher intracellularly as opposed to extracellularly, this is particularly in regard to fatty tissues. Based on the existing in vivo data, the target organs of concern for TBBS are the liver, kidneys, thymus and spleen (MHJW, 1997). The results of the oral repeated dose studies performed in the rat shows systemic distribution. The inhalation study also shows that the substance is able to reach other organs and areas of the lymphatic system. Though no dose-dependent responses were observed. Following oral ingestion, it is likely that TBBS (or hydrolysis products) is distributed via the portal circulation system. The positive sensitisation response observed in the human repeat insult patch test suggests that the hydrolysis products may bind to circulatory proteins. The studies support that there is wide distribution of TBBS after exposure. 


 


Metabolism


The distribution throughout tissues such as the gastro-intestinal tract, and the tendency of TBBS to undergo hydrolysis suggest that initial metabolism will be widespread and non-specific. The results of the oral repeated dose studies in the rat do show microscopic changes in the liver. This may be indicative of further metabolism of hydrolysis products prior to excretion.  As with other category members the main metabolites are expected to be MBT and its conjugates. This is supported by the skin sensitisation results. The other major metabolite after cleavage of the substituent from MBT will be tert-butyl amine. The metabolites are also supported by the predictions of rat liver metabolism given by the OECD QSAR toolbox (v4.5).


 


Excretion


The results of some of the repeated dose oral toxicity studies show changes in the kidneys of rats. This suggests that urinary excretion is a significant route for removal of test material (OECD SIDS 2003). Based on the lipophilicity of the substance and conjugation of MBT, enterohepatic circulation is possible and that some excretion via the faeces is expected.  This clearance mechanism for MBT has been well documented for other category members. There is no data that shows TBBS is found at higher concentrations in breast milk than in blood/plasma. TBBS does not excrete into the hair or nails. Mucus from the lungs would be cleared and excreted or swallowed and undergo the same processes as if administered orally.


 


Potential for accumulation


Based on the information provided from the log P value 3.36 it is possible that TBBS may accumulate. However, due to its extensive metabolism and subsequent excretion, the accumulation potential is thought to be low.  Particles are > 1 µm and thus, accumulation in the lungs may be less likely. The log P is likely too low for the parent or its metabolites to accumulate in the stratum corneum to a significant degree

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

This substance is part of a category; please refer to section 13.2 for further discussion of the toxicokinetic profile.