Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

The carcinogenic potential of MBTS was evaluated in an early carcinogenicity study (Innes 1969) and was not found to be tumorigenic when given orally to mice for 18 months at the maximal tolerated dose; however the study is limited and should be used only for supporting reasons. In addition, no carcinogenic activity was reported in the chronic carcinogenicity study in mice treated with MBT and no clear MBT related carcinogenic activity can be concluded from the chronic rat study.

In the studies by Collins and Strauss (see 7.10.2 epidemiological data) there was no association between exposure to MBT and its derivatives and increased rates of most malignant neoplasms in workers without an exposure to confounding factors. The investigations of Sohahan (see 7.10.2 epidemiological data) revealed contradictory results.

A re-evaluation of published human data has been finished (Environ 2010); with special emphasis of the published data from the Ruabon cohort (Sorahan 2000, 2008, 2009). The re-evaluation of the study data of the Ruabon cohort did not reveal new or compelling evidence supporting a conclusion that MBT may be a human bladder carcinogen. Limitations of this study include difficulties in assigning employees to exclusive exposure specific sub-cohorts, due to the broad cases hampering substance specific evaluation of a possible cancer risk; and combining non-cancer (i.e. benign bladder tumors) with true bladder cancers. The authors of the re-evaluation agreed that some of the members of the Ruabon cohort likely suffered occupational bladder cancer, the evidence remains inadequate to clearly delineate whether any may have been caused by exposure to MBT.

In summary, the re-evaluation of all available epidemiological information cannot identify any specific new evidence that would substantiate the notion that MBT is a bladder carcinogen in humans.

This substance dossier and the IUCLID database of MBT were evaluated by the German competent authority on behalf of the ECHA in 2013. All the above mentioned studies were included in the IUCLID database. A potential concern on carcinogenicity was evaluated German competent authority and it was concluded that MBT is not carcinogenic: „The concern on any need for harmonized classification and labelling of 2-MBT regarding carcinogenicity and/or genotoxicity was clarified. The available data are sufficient and appropriate to conclude that there is no need for a proposal for harmonised classification and labelling of 2-MBT.” (BAuA. 2014. Substance Evaluation Conclusion Document as required by REACH Article 48 for Benzothiazole-2-thiol (2-MBT) EC No 205-736-8; CAS No 149-30-4, dated 17. March 2014).

IARC evaluated MBT in 2016 and concluded that MBT was “probably carcinogenic to humans (Group 2A)” based on limited evidence of carcinogenicity in humans that it causes bladder cancer, and sufficient evidence of carcinogenicity in experimental animals. The exact reasoning of the IARC for the different assessment is not yet available (IARCVolume 115). A short communication cited three relevant studies published in 2008, 1999 and 1988. These studies were reported in the earlier IUCLID dossier during substance registration in 2010 and, consequently, known and evaluated during the substance evaluation in 2013.

 

Volume 115 of the IARC Monographs is not available on the time of the compilation of this dataset. After the release of Volume 115 of the IARC Monographs an assessment of the IARC evaluation will be done.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Carcinogenicity: oral

The carcinogenic potential of MBTS was evaluated in an early carcinogenicity study (Innes 1969). Even through the study was not performed according to present standards, it should be mentioned that MBTS was not found to be tumorigenic when given orally to mice for 18 months at the maximal tolerated dose, which was fixed at 464 mg/kg MBT by gavage (dissolved in 0.5 % gelatine) from day 7 to 28 of age and at 3385 ppm (ca. 237 mg/kg bw/day) in the diet from day 28 for additional 17 months.

There are only limited data from an early cancer study available. A read across approach was conducted with carcinogenicity study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).

Read-across approach with MBT

In a carcinogenicity study (NTP 1988) male and female Fischer 344 rats were administered with MBT for 103 weeks. Groups of 50 male rats were administered 0, 375, or 750 mg/kg 2-mercaptobenzothiazole in corn oil by gavage, 5 days per week for 103 weeks. Groups of 50 female rats were administered 0, 188, or 375 mg/kg 2-mercaptobenzothiazole in corn oil by gavage on the same schedule. For further details on material and methods and non-neoplastic outcome see chapter repeated dose toxicity. The authors of the study reported evidence of increased incidences of monocular cell leukemia, pancreatic acinar cell adenomas, adrenal gland pheochromocytomas, and preputial gland adenomas or carcinomas (combined) in males and increased incidences of adrenal gland pheochromocytomas and piutiary gland adenomas in females. However, the increase in mononuclear cell leukemia, pituitary gland adenomas and pancretic acinar cell adenomas in male rats were increased only in the low dose groups and thus not dose-dependent. The incidences of adrenal gland pheochromocytomas, and prepuitial gland adenomas or carcinomas (combined) were significant increased in low and high dose males. The increase noted was more pronounced in the low dose group than in the high dose group; thus no clear dose-effect relationship was revealed. In high dose females incidences of adenomas of the pituitary gland and adrenal gland pheochromocytomas were significant increased and occurred with significant positive trend. The observed incidences were within the bounds of historical control range. However, the relevance of adrenal gland pheochromocytomas in rats is questionable. Recent data analysis revealed that occurrence of pheochromocytomas in MBT treated rats, is associated with nephrotoxicity associated with endocrine disturbance (Greim 2009). The relevance of this finding for human is questionable. In addition it should be noted that the study is severely comprised by the poor survival rate in male rats, indicating that MTD (maximum tolerated dose) was presumable exceeded, and by the fact of the higher tumor rates in the low dose than in the high dose group in general (absence of a dose-response relationship). The observed differences in the tumor incidences of dosed animals compared to the concurrent controls do not appear to be significant when historical controls are taken into account. The overall rates of individual tumors in treated animals do not exceed the historical range. Overall, no clear carcinogenic activity can be concluded from this study.

In an additional NTP carcinogenicity study male and female B6C3F1 mice were administered with MBT for 103 weeks (NTP 1988). Groups of 50 male and 50 female mice were administered 0, 375, or 750 mg/kg 2-mercaptobenzothiazole in corn oil by gavage, 5 days per week for 103 weeks. For further details on material and methods and non-neoplastic outcome see chapter repeated dose toxicity. The pathological and histopathological incidences of non-neoplastic lesions were in the range of the vehicle control. Neoplastic lesions noted were within the historical control data range.

Overall, no carcinogenic activity was reported in the chronic carcinogenicity study in mice and no clear MBT related carcinogenic activity can be concluded from the chronic rat study.

The Working Group of Volume 115 of the IARC Monographs classified MBT as probably carcinogenic to humans (Group 2A) based on limited evidence of carcinogenicity in humans that it causes bladder cancer, and sufficient evidence of carcinogenicity in experimental animals.

An increase in the incidence of bladder cancer was observed in two studies of chemical plant workers exposed to high amounts of MBT. In studies in experimental animals, an increase in the incidence of tumors was observed in rats and mice exposed orally to MBT.

Volume 115 of the IARC Monographs is not available on the time of the compilation of this dataset. After the release of Volume 115 of the IARC Monographs an assessment of the IARC evaluation will be done.

Justification for classification or non-classification

No classification is justified as this time point according to the classification criteria of regulation no. 1272/2008 (GHS).

This substance dossier and the IUCLID database of MBT were evaluated by the German competent authority on behalf of the ECHA in 2013. All the above mentioned studies were included in the IUCLID database. A potential concern on carcinogenicity was evaluated German competent authority and it was concluded that MBT is not carcinogenic: „The concern on any need for harmonized classification and labelling of 2-MBT regarding carcinogenicity and/or genotoxicity was clarified. The available data are sufficient and appropriate to conclude that there is no need for a proposal for harmonised classification and labelling of 2-MBT.” (BAuA 2014, Substance Evaluation Conclusion Document as required by REACH Article 48 for Benzothiazole-2-thiol (2-MBT) EC No 205-736-8; CAS No 149-30-4, dated 17. March 2014).

Volume 115 of the IARC Monographs is not available on the time of the compilation of this dataset. After the release of Volume 115 of the IARC Monographs an assessment of the data of the IARC evaluation will be done.