Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
745 mg/kg bw/day
Additional information

There are no valid reproduction toxicity data available for SMBT. A read across approach (systemic effects) was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).

Read across with MBT

A two-generation reproductive toxicity study was performed to evaluate the potential effects of MBT on reproduction and development in Sprague-Dawley rats (CMA 1990). The study was designed to determine if MBT has any adverse effects on reproduction functions when fed to F0 and Fl parental animals for a minimum of 70 days prior to mating and continuing until sacrifice. Groups of 28 male and 28 female Sprague-Dawley rats were fed the basal diet or diet containing MBT at concentrations of 2500, 8750, and 15000 ppm. The food was provided ad libitum throughout the study. All F0 and Fl rats were observed daily for signs of overt toxicity, morbidity, or mortality. Body weights were measured weekly for the males throughout the study. For females, body weights were measured weekly prior to confirmation of mating and at specified intervals during gestation and lactation. Food intake was measured on the same days as body weights with the exception of periods of cohabitation when food intake was not measured. F0 and Fl parents were sacrificed and necropsied following weaning of their offspring. Selected tissues and organs were fixed in 10% neutral buffered formalin. Microscopic examination was performed on all tissues collected from the control and 15000 ppm groups. Kidneys from the F0 rats in the other treated groups and liver and kidneys from the Fl rats were also examined microscopically. Liver, kidneys, testes or ovaries from all F0 and Fl parents sacrificed for the scheduled necropsy were weighed. Fl and F2 pups were examined on lactation days 0, 4, 7, 14, and 21. Viability was determined daily. Litter size was reduced to eight pups (four males and four females when possible) on lactation day 4. Body weights were measured on lactation days 1, 4, 7, 14, and 21. Pups dying during lactation were necropsied with special attention given to morphological anomalies. Selection of the Fl generation was performed at weaning. Twenty-eight males and 28 females were selected randomly from each group. Non-selected pups were sacrificed and necropsied. F2 pups were sacrificed and necropsied on lactation day 21. Survival was 100% in all F0 and Fl parental animals. There were no treatment-related clinical signs observed in any of the MBT groups. Food intake, calculated as g/kg/day, was significantly reduced in the 8750 and 15000 ppm groups of the F0 generation during the first week of treatment. Thereafter, food intake was equal to or greater than in the control group. Body weight gain, however, was dose-dependent and significantly reduced in F0 males from all MBT groups and females from mid and high dosage groups during the first week of treatment. Weight gain continued to be slightly reduced for approximately ten weeks for males but not for females. Body weights were significantly reduced in the Fl pups from the mid and high dosage groups and in F2 pups from all MBT groups beginning on day 14 of lactation. Body weights were slightly reduced for Fl pups in the low dosage group and reached statistical significance following weaning. Treatment-related histopathological changes were seen in the kidneys of both F0 and Fl animals. Brown pigment was observed in the lumen and epithelial cells of the proximal convoluted tubules in males and females in the mid and high dosage groups, with a greater incidence in the males than in females. Cortical tubular basophilia and alpha 2 µ-globulin inclusions in the epithelial cells of the proximal convoluted tubules occurred in males from all groups with a higher incidence in the treated groups. In addition, absolute and relative kidney weights were significantly increased for F0 and F1 males in the mid and high dosage groups. Microscopic changes, consisting of hepatocyte hypertrophy, occurred in the livers of the Fl animals from the 15000 and 8750 ppm groups, at a higher incidence in males than in females. The increased workload due to continuous exposure to the test article, apparently led to hepatic hypertrophy. Furthermore, histopathological changes correlated with a significant increase of liver weight in the males in the mid and high dosage groups and for females in the high dosage group. Hepatic lesions, noted in the Fl animals are probably related to a greater intake of the test article, since Fl pups started to eat the test diet at approximately 14 days of age, while the F0 animals were administered MBT beginning at seven weeks of age. There were no other treatment-induced changes in any of the organs examined microscopically from rats in the MBT groups of either the F0 or F1 generation. There was no evidence of adverse reproductive effects in the F0 or Fl generation, following treatment with MBT for a minimum of 70 days prior to breeding, during breeding and continuing until sacrifice. Reproductive parameters, including precoital interval, and copulation and fertility indices, pregnancy percentage and gestation length, were similar in the control and treated groups of both the F0 and Fl generations. Litter size and litter viability were not affected by the administration of MBT to parental animals.

The authors concluded that a dosage level of 15000 ppm was considered a No Adverse Effect Level for reproductive toxicity. Minimal to mild toxic effects were observed in parental animals from all MBT groups. These effects were more prominent in the Fl generation due to a greater intake and longer exposure to the test article.

In conclusion:

The potential reproductive toxicity of MBT was evaluated in a two-generation study in rats (CMA 1990). There was no evidence of adverse reproductive effects in the F0 or Fl generation, following treatment with MBT for a minimum of 70 days prior to breeding, during breeding and continuing until sacrifice. Reproductive parameters, including precoital interval, and copulation and fertility indices, pregnancy percentage and gestation length, were similar in the control and treated groups of both the F0 and Fl generations. Litter size and litter viability were not affected by the administration of MBT to parental animals. Nevertheless, mild toxic effects were noted in animals of the F0, Fl and F2 generations. A significant and dose-dependent reduction of body weight gain occurred during the first week of treatment in F0 males from all MBT groups and females from the 8750 and 15000 ppm groups. Weight gain continued to be slightly reduced in F0 males for approximately ten weeks. F0 females from all MBT groups had a reduced weight gain during the first week of gestation, with statistical significance noted in the low and high dosage groups. Food intake, calculated as g/kg/day was significantly reduced in the 8700 and 15000 ppm groups of the F0 generation during the first week of treatment. Thereafter, food intake was equal to or greater than in the control group. Similar effects on body weights and food consumption were also evident in the Fl and F2 generations. Body weights were reduced in the Fl and F2 animals from all MBT groups in a dose-dependent fashion, beginning on lactation day 14. Food consumption calculated as g/kg/day, was greater in the Fl parental animals from the treated groups than in the control group. Histopathological changes occurred in the kidneys of males and females from both F0 and Fl generations. Brown pigment was observed in the lumen and epithelial cells of the proximal convoluted tubules with a greater incidence in males than in females. The presence of brown pigment in the lumen suggests a renal route of excretion rather than a toxic effect. Cortical tubular basophilia and alpha 2µ-globulin inclusions were seen with higher frequency in the males from the treated groups than in the control group.


Short description of key information:
There are no valid reproduction toxicity data available for SMBT. A read across approach (systemic effects) was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).
The findings of the two-generation study in rats demonstrated that MBT did not have any adverse effects on reproductive functions of the F0 or Fl generation. Thus, a dosage level of 15000 ppm was determined to be a No Adverse Effect Level for reproductive toxicity. Minimal to mild toxic effects occurred in all treated groups in both F0 and Fl parental animals. The effects were more prominent in the Fl animals due to a greater intake and longer exposure to the test article.

Effects on developmental toxicity

Description of key information
There are no developmental toxicity study data available for SMBT. A read across approach (systemic effects) was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).
The developmental toxicity potential of MBT was evaluated in Sprague-Dawely rats (CMA 1989) and in New Zealand White rabbits (CMA 1989).
The oral administration of 50, 150, or 300 mg/kg/day of MBT to pregnant New Zealand White rabbits during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at a level of 300 mg/kg/day as slightly decreased body weight gain and slightly elevated liver weight. In the developmental toxicity study with rats (CMA 1989), the oral administration of MBT to pregnant Sprague-Dawely rats induced moderate maternal toxicity at a level of 1800 mg/kg/day expressed by pharmacotoxic signs, reduced body weight gains, and food intake. Pharmacotoxic signs were the only indication of treatment-related effects at a dosage level of 1200 mg/kg/day. A dosage level of 300 mg/kg/day was determined to be a No Adverse Effect Level for maternal toxicity. MBT administered during major organogenesis at dosage levels of 300, 1200, or 1800 mg/kg/day did not induce any developmental toxicity or teratogenicity in treated rats.
Based on the findings of these developmental toxicity studies a NOAEL developmental of 300 mg/kg bw and day is suggested, which based on the findings from the rabbit study.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Additional information

There are no developmental toxicity study data available for SMBT. A read across approach (systemic effects) was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).

Read across with MBT

The developmental toxicity of MBT was evaluated in a teratology study with pregnant Sprague-Dawley rats (CMA 1989). The test substance was orally administered to pregnant Sprague-Dawely rats during the critical period of organogenesis. Groups of 26 rats, presumed pregnant, were treated with MBT at dosage levels of 300, 1200, and 1800 mg/kg/day. MBT was suspended in corn oil and administered by gavage at a volume of 10 ml/kg. A concurrent control group, consisting of 26 rats, received corn oil at an equivalent dosage volume. The treatment was performed from gestation day 6 through gestation day 15. All rats were observed daily for signs of toxicity. Body weights and food consumption were measured on gestation days 0, 6, 9, 12, 16, and 20. Caesarean sections were performed on gestation day 20. Foetuses were weighed and examined for external, visceral, and skeletal anomalies. Maternal toxicity was evident in the 1800 mg/kg/day group and manifested by clinical signs (salivation, dark red material around mouth, urine staining, and decreased activity), body weight losses and reduced food consumption between gestation days 6 and 9. Clinical signs (salivation, urine staining, and dark material around mouth) were the only indication of treatment-related effects in the 1200 mg/kg/day group. There were no treatment-related effects noted in the 300 mg/kg/day group. Foetal viability was not affected by the administration of MBT during the critical period of organogenesis, in that the mean number of viable foetuses was slightly greater in the treated groups in relation to the control group. The only possible effect of treatment seen in the reproductive or foetal parameters was a statistically significant increase in post-implantation loss in the 300 and 1800 mg/kg/day groups. The biological significance of this finding was deemed equivocal for the 1800 mg/kg/day dosage group and biologically insignificant for the 300 mg/kg/day group. Substantiating and concurrent observations included no statistically significant effect of treatment on post-implantation loss in the 1200 mg/kg/day group as well as no treatment-related effect on foetal weights, sex ratio and morphological variations or malformations. The authors concluded, that oral administration of 1800 mg/kg/day of MBT to pregnant Sprague-Dawley rats induced maternal toxicity exhibited by clinical signs, reduced body weight gain and food intake. Clinical signs of toxicity were also evident in the 1200 mg/kg/day group. A dosage level of 300 mg/kg/day was determined to be a No Adverse Effect Level for maternal toxicity. MBT was neither developmentally toxic nor teratogenic at dosage levels of 300, 1200, or 1800 mg/kg/day, thus a NOAEL for developmental toxicity of 1800 mg/kg/day is suggested.

Another teratology study was performed with New Zealand White rabbits (CMA 1989). The objective of this study was to evaluate potential toxic and teratogenic effects of 2-mercaptobenzothiazole (MBT) when administered orally to pregnant rabbits during the critical period of organogenesis. The experimental design consisted of three MBT treated groups and a concurrent control group. Each group was comprised of 20 artificially inseminated New Zealand White rabbits. Dosage levels selected for this teratology study were 50, 150, and 300 mg/kg/day. MBT was suspended in 1% methylcellulose and administered at a volume of 2 ml/kg. Control animals received 1% aqueous solution of methylcellulose at an equivalent dosage volume. Treatment was performed from gestation day 6 through gestation day 18. All rabbits were observed daily for signs of overt toxicity. Body weights were measured on gestation days 0, 6, 9, 12, 15, 19, 24, and 29. Food consumption was measured daily and reported for the specified intervals. Caesarean section was performed on gestation day 29. Intrauterine survival was evaluated and foetuses were examined for external, visceral, and skeletal anomalies. Oral administration of MBT to pregnant rabbits at a level of 300 mg/kg/day induced maternal toxicity as expressed by reduced body weight gain during treatment (day 6 to 19: -63 % vs. control) and slightly elevated liver weight, absolute (+ 7 %) or relative (+ 4 %) to final body weight. This toxicity became apparent upon visual inspection of individual body weight gain data particularly during the last days of treatment (gestation days 15-19) for this group when compared to the control group. During this period, six treated does had body weight losses greater than 150 grams while no control dam lost this magnitude of body weight. Lower dosage levels of MBT (50 and 150 mg/kg/day) did not produce any evidence of maternal toxicity. A single abortion was noted in the 150 mg/kg/day group on gestation day 19 and a premature delivery occurred in the 300 mg/kg/day group on gestation day 29, prior to the scheduled caesarean section. A single incidence of abortion was noted in the range-finding study at levels of 600 and 1000 mg/kg/day (CMA 1989). However, the biological and toxicological significance of the abortion and premature delivery in the present study is equivocal, knowing that abortions or premature deliveries are common in rabbits; a dose-related pattern was not evident (in particular, the time of occurrence); abortions were not noted in the range-finding study at levels of 150 or 300 mg/kg/day. One rabbit in the 300 mg/kg/day group died on gestation day 13. Post-mortem findings indicated that the death occurred following an intubation error (semi-solid yellow contents in trachea).

The administration of MBT during the critical period organogenesis at dose levels of 50, 150, or 300 mg/kg/day did not induce any developmental toxicity or teratogenicity, in that all foetal data, including viability, mean body weight, malformations, and variations were comparable between the MBT and control groups. The authors concluded that, oral administration of 50, 150, or 300 mg/kg/day of MBT to pregnant New Zealand White rabbits during major organogenesis did not induce any developmental toxicity or teratogenicity. Thus, based on the selected dose range evaluated and the findings of this study a NOAEL developmental toxicity of 300 mg/kg bw and day is suggested. Maternal toxicity was evident only at a level of 300 mg/kg/day as slightly decreased body weight gain and slightly elevated liver weight.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).

Additional information