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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
Accpetable documented study report with restriction (test substance purity not indicated; 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 was presumably not given. The biologically relevance of findings from this study, especially systemic effects are questionable, whereas local effects noted in the inhalation study could be used for supporting purpose.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Principles of method if other than guideline:
In a four-week pilot inhalation study male and female rats were exposed to the dust atmosphere of Santocure NS 6 (N-tert-butylbenzothiazole-2-sulphenamide) hours per day, 5 days per week for 20 or 21 exposures during a 29-day experimental period. The mean nominal exposure concentrations for groups III, IV and V were 0.058, 0.172 or 0.524 mg/liter, respectively. The equivalent aerodynamic diameter was 8.4 micrometers.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-tert-butylbenzothiazole-2-sulphenamide
EC Number:
202-409-1
EC Name:
N-tert-butylbenzothiazole-2-sulphenamide
Cas Number:
95-31-8
Molecular formula:
C11H14N2S2
IUPAC Name:
N-(1,3-benzothiazol-2-ylsulfanyl)-2-methylpropan-2-amine
Details on test material:
Santocure NS, lot no. MIC 270582

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
8.4 µm
Remarks on MMAD:
MMAD / GSD: aerodynamic mass medium diameter: 8.4 micrometer with a geometric standard deviation of 4.31
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of the airborne dusts in the chamber atmosphere was determined analytically using the fiberglass filter sampling technique.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.0, 0.0024, 0.029, and 0.084 mg/l
Basis:

No. of animals per sex per dose:
10 animals per dose and sex
Control animals:
yes
Details on study design:
Post-exposure period: no
Positive control:
None.

Examinations

Observations and examinations performed and frequency:
Clinical signs (ocular and nasal irritation, respiratory distress), body weights, food consumption, clinical chemistry, hematology, biochemistry, urinalysis.
Sacrifice and pathology:
At the termination of the study the rats from all groups were sacrificed for gross and histopathological examinations.
Statistics:
All statistical analysis compared the treatment group with the control group.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Nasal irritation was observed in the rats and ranged in severity from slight to marked. The symptom was usually present after exposure and had generally disappeared by the following morning. The severity of nasal irritation appeared to be concentration dependent during the first half of the study, several rats in the highest dose group exhibited an urogenital discharge. This symptom was observed after exposure and was still apparent the following morning. Alopecia was observed in two rats of the highest dose group.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No effects.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
at 0.029 and 0.084 mg/l: SGOT values for males and females were significant elevated compared to control (II).
at 0.0024 mg/l: SGOT values were comparable to control all other parameters appeared comparable to one or both control groups.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effects.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Some variations in absolute and rel. weights, but the variations did not appear to be dose dependent and there were no compound related microscopic alterations associated with the involved tissue, therefore the biological signifcance of the variations could not be determined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross lesions interpreted as compound induced observed in any animal at necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
0.084 mg/l: brown pigments within sinusoidal macrophages in lymph nodes (6/20)was slightly increased when compared to controls (2 control I, 1 control II)concurrent erythrophagocytosis in the lymph nodes was also slightly increased in the Santocure NS treated group (4/20) as compared to controls (0 control T, 1 control II) Very slight to moderate focal to multifocal hepatocellular necrosis was observed in 3/20 animals; an associated acute inflammatory infiltrate was present in 2 of the 3 affected animals. This lesions was not present in controls While the previously described lesions may represent a compound effect, they have been observed in control rats at the facility and therefore the possibility that they are spontaneous in origin cannot be excluded.

The occurence and incidence of all other microscopic lesions were similar to that observed in controls.
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
other:
Effect level:
0.029 mg/L air
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Nominal concentrations: 0.058, 0.17 and 0.52 mg/l


Analytical concentrations: mean analytical concentrations: 0.0024, 0.029 and 0.084 mg/l


Gravimetric concentrations: mean gravimetric concentrations: 0.0024, 0.028, 0.088 mg/l


Dust particle size distribution analyses: the equivalent aerodynamic mass medium diameter: 8.4 µm , geometric standard deviation of 4.31


 


Clinical studies Appearance and general behavior: Nasal irritation was observed in the rats and ranged in severity from slight to marked. The symptom was usually present after exposure and had generally disappeared by the following morning. The severity of nasal irritation appeared to be concentration dependent during the first half of the study, several rats in the highest dose group exhibited an urogenital discharge. This symptom was observed after exposure and was still apparent the following morning. Alopecia was observed in two rats of the highest dose group.


 


Body weights: no effects.


Food consumption: no time or test material related differences were observed.


 


Hematology: no effects.


 


Blood chemistry:


at 0.029 and 0.084 mg/l: SGOT values for males and females were significant elevated compared to control (II).


at 0.0024 mg/l: SGOT values were comparable to control all other parameters appeared comparable to one or both control groups.


 


Urinalysis: no effects.


 


Gross pathology: No gross lesions interpreted as compound induced observed in any animal at necropsy.


 


Organ weights: Some variations in absolute and rel. weights, but the variations did not appear to be dose dependent and there were no compound related microscopic alterations associated with the involved tissue, therefore the biological signifcance of the variations could not be determined.


 


Histopathology: 0.084 mg/l: brown pigments within sinusoidal macrophages in lymph nodes (6/20)was slightly increased when compared to controls (2 control I, 1 control II)concurrent erythrophagocytosis in the lymph nodes was also slightly increased in the Santocure NS treated group (4/20) as compared to controls (0 control T, 1 control II) Very slight to moderate focal to multifocal hepatocellular necrosis was observed in 3/20 animals; an associated acute inflammatory infiltrate was present in 2 of the 3 affected animals. This lesions was not present in controls While the previously described lesions may represent a compound effect, they have been observed in control rats at the facility and therefore the possibility that they are spontaneous in origin cannot be excluded.


 


The occurence and incidence of all other microscopic lesions were similar to that observed in controls.


 


Histological examinations of treated animals (highest dose group) of the nasal turbinate area, trachea, lung and olfactory bulb revealed no biologically relevant differences compared to the controls.

Applicant's summary and conclusion

Conclusions:
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 was presumably not given. The biologically relevance of findings from this study, especially systemic effects are questionable.
Executive summary:

In a four-week pilot inhalation study male and female rats were exposed to the dust atmosphere of Santocure NS 6 (N-tert-butylbenzothiazole-2-sulphenamide) hours per day, 5 days per week for 20 or 21 exposures during a 29-day experimental period. The mean nominal exposure concentrations for groups III, IV and V were 0.058, 0.172 or 0.524 mg/liter, respectively. The equivalent aerodynamic diameter was 8.4 micrometers.

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 was presumably not given. The biologically relevance of findings from this study, especially systemic effects are questionable.