(benzothiazol-2-ylthio)acetic acid

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Description of key information

There are no studies available in which the toxicokinetic properties of (Benzothiazol-2-ylthio) acetic acid are investigated.

The test substance is a light yellow to white powder at room temperature and has a molecular weight of about 225 g/mol. The molecular structure of the test substance comprises2-Mercaptobenzothiazol, linked withacetic acidmolecule via the sulfur.The experimental determined water solubility is 133 mg/L (20°C) with a pH of 3.2 (1% m/m in water). The Log Pow is determined 1.6 and the vapor pressure is low with 0.001 Pa (20°C).

Toxicity profile:

The acute oral toxicity of the test substance (LD50oral) is determined to be 1580 mg/kg body weight for female and male rats. The acute dermal toxicity (LD50 dermal) of the test substance is greater than 2000 mg/kg body weight in female and male rats and it is not a skin sensitizer. The test substance is locally not skin irritant but it causes serious eye damage.

Repeated oral dosing of the test substance for 28 days at doses of 100 mg/kg bw/day resulted in increased kidney and liver weights. After repeated oral administration to rats via gavage in a dose range-finding study the test substance induced clinical signs such as hypo activity and dehydration at doses greater than 150 mg/kg bw/day. At dose level of 225 mg/kg bw/day signs of hypo activity, piloerection and dehydration observed prior to deaths in both sexes. In a reproduction/ developmental toxicity screening study in rats according to OECD 421 in the male population, the 43-day treatment resulted, beside other changes, in increased kidney and adrenal weights at the 125 mg/kg bw /day dose group. In females, up to the highest dose tested (125 mg/kg bw /day) no treatment-related adverse changes were observed. In repeated dose studies, the water uptake was significantly higher at all dose groups in both sexes compared to controls.

Absorption and Distribution

When orally applied, passive absorption of (Benzothiazol-2-ylthio) acetic acid is the likely favored way of uptake in the GI tract due to the small size and the low Log P_owof the molecule (please refer to Guidance on information requirements and chemical assessment, June 2017, Chapter R.7.12. 2.1). After absorption the test substance is considered to be distributed through the whole body. Indication for this assumption is e.g. seen after a single oral application of the test item when all animals showed a reduced activity during the first 24 hours. Cachexia was observed in animals which died during observation day 5 and 7 in a dose range finding study for repeated dose treatment. Liver and kidney effects can be observed after uptake of the substance to the whole body e.g. by the increased relative kidney and liver weights after 28 days of repeated oral dosing, which are decreasing to normal after a recovery phase of 14 days. The altered kidney weights were not associated with any related microscopic changes. Since systemic effects were observed in course of repeated dose studies at doses greater 100 mg/kg bw/day a considerable amount of the substance is proved to be bioavailable. 

Dermal uptake is assumed to be lower than oral uptake due to the higher LD₅₀value in acute dermal toxicity study compared to acute oral toxicity study and the ionic character of the test substance.Therefore, lower systemic bioavailability is assumed.

Metabolism:

Based on findings from available repeated dose studies, an increase in liver weight indicates the liver being actively involved in metabolism of the test substance, followed by a decrease to normal liver weights after a 14-day recovery period. This recovery finding indicates the liver weight effects are not persistent. In silico considerations were used to predict the metabolic pathways of enzymatic oxidation and glucuronidation and the metabolites and/or catabolic end products. Hydroxylation is possible at the phenyl ring of the2-Mercaptobenzothiazolmoiety prior to further conjugation steps.Using the combined in silico analysis including METEOR Nexus (version 2.0.2 Lhasa Ltd.) for the prediction of metabolic fate and subsequent evaluation through DEREK Nexus (version 4.0.5, Lhasa Ltd.) for structural alerts, it could be demonstratedthat Sulphoxide formation is expected to be one of the primary metabolizing steps and Glucuronidation at theacetic acidmoiety another metabolizing step. Glucuronidation and other conjugation (e.g. glucamine conjugation) seem to be the most probable pathways for Phase II metabolism. Glucuronides are good water soluble and thus, the major excretion way for the (Benzothiazol-2-ylthio) acetic acid is predicted via urine. The bio-accumulation potential of the test substance is thus considered to be low.Schematic metabolism assumed for (Benzothiazol-2-ylthio) acetic acid based on in silico consideration using DEREK / METEOR analysis can be outlined as shown in Figure 1 of Kinetic Assessment (see attached document at Section 13 of this IUCLID file).

Excretion:

Metabolites of (Benzothiazol-2-ylthio) acetic acid in form of e.g. Glucuronides are good water soluble and thus, the major excretion way for the (Benzothiazol-2-ylthio) acetic acid is predicted via urinary way. Because of the measured Log P_owof 1.6 the potential of the test substance for bioaccumulation is considered to be low.

Conclusion

Due to the small size and the low Log P_owof the molecule, passive absorption of (Benzothiazol-2-ylthio) acetic acid is the favored way of uptake in the GI tract. Systemic availabilityvia dermal penetration is

assumed to be low. Sulphoxide formation is expected to be one of the primary metabolizing steps and Glucuronidation at theacetic acidmoiety another metabolizing step. Glucuronidation and other conjugation (e.g. glucamine conjugation) seem to be the most probable pathways. Glucuronides are good water soluble and thus, the major excretion way for the (Benzothiazol-2-ylthio) acetic acid is predicted via urine. From the available data of (Benzothiazol-2-ylthio) acetic acid and the in silico analysis it can be concluded, that the substance is systemically bioavailable, metabolic degraded via enzymatic oxidatation and Glucuronidation and at least excreted via urine. Thus, the bio-accumulation potential of the test item is assumed to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

none