Zinc di(benzothiazol-2-yl) disulphide

Endpoint summary

Additional information

There are no experimental toxicokinetic data available for zinc 2-mercaptobenzothiazole (ZMBT; CAS 155-04-4). This statement is therefore based on existing information (physical-chemical data and toxicological data) of zinc 2-mercaptobenzothiazole and on toxicokinetic data for the hydrolysis product 2-mercaptobenzothiazole (MBT; CAS 149-30-4), and on REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Zinc 2-Mercaptobenzothiazole (CAS 155-04-4, EC 205-840-3, ZMBT) reacts in aqueous solutions under acidic conditions, forming 2-Mercaptobenzothiazole (CAS 149-30-4, EC 205-736-8, MBT) and Zinc ions (Zn2+, CAS 23713-49-7). Test results show the complete hydrolysis of ZMBT to MBT at pH 3 in the time needed for sample preparation between acidification and recording of NMR-spectra (< 9 minutes). Repeated NMR-spectra after 3 and 29 minutes show no trace of residual ZMBT, as well as no further reaction of the degradation product MBT (Currenta, 2019). In a supporting study, a non-GLP extraction and high performance thin layer chromatography experiment was performed on ZMBT (155-04-04) to confirm rapid hydrolysis to MBT (CAS 149-30-4). Following short time extractions of a sample of ZMBT with either water (neutral pH) or 3% acetic acid and immediate chromatography it was qualitatively shown that hydrolysis of ZMBT to MBT under acetic conditions can be detected after very short periods of time (Currenta 2019).

Data on stomach pH values for different species are given in the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c (June 2017). In humans the median pH in the anterior/posterior portion of the stomach is 2.7/1.9, respectively. Thus, ZMBT would be rapidly hydrolyzed to MBT after ingestion and thus, MBT can be considered as the relevant toxicity driver in humans. In rats the stomach pH is somewhat higher, with 5 in the anterior and 3 in the posterior portion. Read-across from the MBT studies follows thus a worst-case approach. (for further details see Read-Across Justification (Currenta, 2020).

General considerations:

Generally, solids as ZMBT and MBT have to dissolve before they can be absorbed in the gastro-intestinal tract. Since both substances are poorly soluble in water systemic availability after incidental oral uptake is limited. Chemicals with molecular weights below 500 and with a logP between1 and 4, however, are favourable for absorption. From this point of view absorption of the hydrolyzation product MBT with a MW of 167.25 and a log P of 2.47 can be expected in experimental settings. This view is supported by toxicokinetic investigations and by signs of systemic toxicity after oral treatment of experimental animals with high MBT doses.

On the other hand the physical-chemical properties of ZMBT are not favourable for absorption in the gastro-intestinal tract, with a MW of 397.9, a log P of 5.2 and the proof of complete hydrolysis at acid pH values. It can thus be expected that systemic toxicity after oral treatment of experimental animals with high ZMBT doses are a consequence of the toxic properties of the systemically available MBT.

 

Estimation of absorption based on experimental toxicokinetic data for MBT and conclusion for ZMBT:

The toxicokinetic fate of MBT was evaluated in several studies in rats and guinea pigs (CMA 1986, CMA 1987, Nagamatsu 1979). The dermal absorption of MBT is low. In topically treated rats percutaneous absorption rates of 16.1 % to 17%, in guinea pigs of 38.4%, were measured. Since the MW of ZMBT is much higher than that of MBT, dermal absorption of ZMBT is considered to be the same or even lower than that of MBT.

Orally administered MBT was readily absorbed and excreted, whereas excretion was primarily in the urine, with only small amounts in faeces (CMA 1986, 1987). Due to the rapid hydrolysis of ZMBT to MBT and Zn2+ under acidic conditions the oral absorption rate of MBT is considered relevant for ZMBT.

Recovery data after oral or intravenously administered MBT did not indicate that appreciable amounts of radioactivity from 14C-labeled MBT were retained in tissues other than blood. Metabolism studies revealed a glucuronide, a glutathione conjugate, the mercapturic acid as well as a sulphate and dibenzothiazyl disulfide as metabolites of MBT in urine. Due to the rapid hydrolysis of ZMBT to MBT and Zn2+ under acidic conditions the oral absorption rate of MBT is considered relevant for ZMBT.

Estimation of absorption based on experimental toxicokinetic data for Zn2+:

The second component of ZMBT is the zinc ion Zn2+. Zn2+ is an essential trace element for human nutrition and ubiquitous in biological systems including humans. The human body has efficient mechanisms, both on systemic and cellular levels, to maintain zinc homeostasis over a broad exposure range. Consequently, zinc has a rather low toxicity. On the other hand, zinc deficiency is a condition with broad occurrence and potentially profound impact (Plum et al., 2010). Toxicity and impacts on human health of zinc has been extensively evaluated by the EU (EU RAR, 2004), the Agency for Toxic Substances and Disease Registry (ATSDR, 2006) and in reviews of Plum et al. (2010), and Chasapis et al. (2020).

According to the EU Risk Assessment report (2004) an oral absorption rate of Zn2+ of ca. 20 % is suggested, whereas for the inhalation route an absorption rate of 40% is assumed. The dermal absorption of Zn2+ is low. A dermal absorption rate of 2 % was suggested (EU risk assessment 2004).

Comparison of toxicological data for ZMBT and MBT:

High similarities in mammalian toxicity were noted in toxicological studies performed with MBT and ZMBT (see Table below). The acute oral toxicity in rats and the acute dermal toxicity in rabbits of ZMBT and MBT is very low, indicated by oral LD50 values of >= 3800 mg/kg bw and dermal LD50 values > 7940 mg/kg bw, respectively. Both substances showed no skin and no eye irritating potential in rabbits. For both substances a moderate skin sensitizing potential was revealed. No mutagenic potential was indicated for ZMBT and MBT in bacterial mutation assays and in mammalian cell gene mutation tests. For both substances increased numbers of chromosomal aberrations were recorded in vitro, an observation that could be disproved as in vitro artefact, as in vivo micronucleus assays with negative outcome for both substances showed not mutagenic potential in vivo.  

In conclusion, the available toxicokinetic and toxicity studies with MBT and the similarity of toxicological effects obtained with MBT and ZMBT support the assumption that MBT is the driver of toxicity after treatment with ZMBT.