N-(1,1-dimethylethyl)bis(2-benzothiazolesulfen)amide

Endpoint summary

Description of key information

For the oral route, two well-documented K2 studies (of which one is the range-finder for the other) are available. The NOAEL for males and females in this study was considered to be 15000 ppm after 90 days of feeding, which corresponds to actual received doses of ca. 1093 mg/kg bw d for males and 1334 mg/kg bw d for female animals.
For the inhalatory and dermal route of administration no studies on TBSI are available. Nevertheless, for each of both exposure routes the adverse effects of read across substance TBBS have been assessed. 
The inhalation toxicity of TBBS was examined in a subacute inhalation study (Monsanto Co. 1981). Due to the limitations of the test protocol that was used the assessment of systemic effects is questionnable and, as a consequence, only the local inhalation effects are considered to be reliable. Based on the fact that 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. 
A 21-day dermal toxicity study of TBBS showed no systemic effect up to the highest dose level (2000 mg/kg bw/d), which can be regarded as the systemic NOAEL. Local effects consisted of acanthosis, hyperkeratosis and dermal inflammatory cell infiltrate in the treated skin of rabbits from the 2000 mg/kg bw/d group, but not in the lower dosed animals.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 093 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subchronic

Species:

rabbit

Additional information

Two well-documented K2 studies (of which one is the range-finder for the other) are available. The study is performed according to GLP. Testing protocol is described in detail, but only general reference to internationally accepted testing guidelines is made. The NOAEL for males and females in this study was considered to be 15000 ppm after 90 days of feeding, which corresponds to actual received doses of ca. 1093 mg/kg bw d for males and 1334 mg/kg bw d for female animals. The NOEL in this study was considered to be 15000 ppm for males and 2500 ppm for females, based upon slight, non-significant decreases in body weights. Actual ingested doses were calculated from the dietary doses using daily food intake data recorded during the study.

For the inhalatory and dermal route of administration no studies on TBSI are available. Nevertheless, for each of both exposure routes the adverse effects of read across substance TBBS have been assessed.

The inhalation toxicity of TBBS was examined in a subacute inhalation study (Monsanto Co. 1981). The study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable; whereas local effects noted in the inhalation study will be used as supporting evidence. Based on the fact that 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.

The dermal toxicity of the read across substance TBBS was evaluated in a 21-day dermal toxicity study (Monsanto Co. 1981). No death or systemic toxicity was indicated in any of the treated animals. No effects on body weight or dermal irritation were noted. Some incidental changes in haematology and biochemistry was observed. No compound related macroscopic lesions or statistically significant organ weight variations were found in this study. However, microscopically, compound-related lesions consisting of acanthosis, hyperkeratosis, and dermal inflammatory cell infiltration were seen in the treated skin of rabbits from the 2000 mg/kg bw d dose group.

Justification for read-across: dermal

Read-across from experimental results available for TBBS is considered to be valid after comparison of the intrinsic physicochemical properties of both substances and based on the comparable chemical reactivity of TBBS and TBSI.

 

The dermal uptake of solid substances is mainly determined by the molecular weight, log Pow and water solubility of the substance (source: Toxicological risk assessment of chemicals – A practical guide, E. Nielsen et al., Informa Healthcare, 2010).

·     The molecular weight of TBBS (238 g/mol) and that of TBSI (404 g/mol) both enable dermal uptake. Dermal uptake is less favourable at higher molecular weights.

·     The Log Pow of TBBS is ca. 3.9, whereas TBSI has a log Pow of ca. 6.7. According to the above noted source, the dermal uptake is optimal when the Log Pow is 2-3. At Log Pow > 4, the substance will be taken up into the stratum corneum, but further migration into the epidermis is slow. At Log Pow > 6, both the uptake in the stratum corneum and the migration into the epidermis are considered to be slow.

·     The water solubility of TBBS is < 1 mg/L, and the water solubility of TBSI is even a factor 100 lower. A lower water solubility results in a worse partitioning from the stratum corneum into the epidermis.

 

From the above comparison of physicochemical properties it can be concluded that the dermal uptake of TBSI will be lower than the dermal uptake of TBBS. Furthermore, due to the comparable chemical reactivity of TBBS and TBSI, it can be expected that both substances will exert the same toxicological effects.

Justification for read-across: inhalation

The inhalatory uptake of solid substances is mainly determined by the vapour pressure, particle size, Log P_o/wand water solubility of the substance (source: Toxicological risk assessment of chemicals – A practical guide, E. Nielsen et al., Informa Healthcare, 2010).

 

·     The vapour pressure of TBSI and TBBS are comparable: 5,3*10^-6and 2,1*10^-6hPa, respectively. For substances having such a low vapour pressure, exposure to vapours is not considered relevant.

·     Both TBSI and TBBS contain particle fractions with a particle size < 100 µm, and as such can form inhalable dusts.

·     As the water solubility is very low for both substances, the substances will not have a high tendency to diffuse/dissolve into the mucus lining of the respiratory tract, from which absorption directly across the respiratory tract epithelium would be possible. On the contrary, such poorly soluble dust particles mainly are removed from the respiratory tract by mucociliary clearance or by phagocytosis-based mechanisms.

 

From the above comparison of physicochemical properties it can be concluded that the inhalatory uptake of TBSI will be comparable to the inhalatory uptake of TBBS. Furthermore, due to the comparable chemical reactivity of TBBS and TBSI, it can be expected that both substances will exert the same toxicological effects.

 

Justification for classification or non-classification

Conclusive, but not sufficient for classification