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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
other: Guidelines for 28-day repeated dose toxicity testing of chemicals (Japan)
Deviations:
no
Principles of method if other than guideline:
N-cyclohexyl-2-benzothiazolesulfenamide was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 25, 80, 250 or 800 mg/kg bw/day.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-cyclohexylbenzothiazole-2-sulfenamide
EC Number:
202-411-2
EC Name:
N-cyclohexylbenzothiazole-2-sulfenamide
Cas Number:
95-33-0
Molecular formula:
C13H16N2S2
IUPAC Name:
N-(1,3-benzothiazol-2-ylsulfanyl)cyclohexanamine
Test material form:
solid: granular
Remarks:
greyish white
Details on test material:
Purity: 98.8 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Vehicle control
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
80 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
800 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Six per dose and sex.
Control animals:
yes, concurrent vehicle
Details on study design:
Exposure period: 28 days
Post-exposure period: with and without 14 days recovery period

Examinations

Observations and examinations performed and frequency:
Signs of general condition,food consumption, body weight gain, Hematoloty, urinalysis
Sacrifice and pathology:
Organs weights, histopathological examination.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Signs of loss of general condition like piloerection and soiled fur were observed in females of the 800 mg/kg bw group.
Mortality:
no mortality observed
Description (incidence):
All animals survived until the end of the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Suppression of food consumption and body weight gain was noted in females of the 250 mg/kg group and males and females of the 800 mg/kg bw group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Suppression of food consumption and body weight gain was noted in females of the 250 mg/kg group and males and females of the 800 mg/kg bw group.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Shortening of prothrombin time in males of the 250 and 800 mg/kg bw groups.  
Decreased hematocrit, reticulocyte count and platelet count in females of the 800 mg/kg bw group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Total protein content was decreased in males of the 250 and 800  mg/kg bw groups.
Chloride levels were reduced in males and females of the  800 mg/kg-group. Calcium level was elevated and sodiumlevel reduced in  females of the 800 mg/kg bw group.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Increase of ketone bodies in males of 250 and 800 mg/kg bw groups.  
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Distended cecum in females of the 800 mg/kg bw group. Increased relative kidney weights in males and females of the 800 mg/kg bw group.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Increased deposition of hyaline droplets in the renal proximal tubular epithelium in males of the 250 and 800 mg/kg w groups. After the 14 days recovery the histopathological changes in the kidneys tended to recover and the other substance-related changes had disappeared.
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
80 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on signs of coagulopathy and kidney adversity in male rats, suppression of food consumption and body weight gain in female rats
Key result
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
haematology
histopathology: non-neoplastic
Key result
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain

Any other information on results incl. tables

All animals survived until the end of the study.


 


Males:


25, 80 mg/kg bw: no adverse effects (decrease of GPT* at 25, and 80 mg/kg bw)


250 mg/kg bw: increase of ketone bodies, shortening of the prothrombin time, on blood chemical examination: total protein was decreased,


Histopathology: an increase in deposition of hyaline droplets in the renal proximal tubular epithelium.


800 mg/kg bw: Suppression of food consumption and body weight gain, urin analysis revealted an increase of ketone bodies,shortening of the prothrombin time,on blood chemical examination: total protein was decreased, reduced chloride levels,


Histopathology: an increase in deposition of hyaline droplets in the renal proximal tubular epithelium, increase of the relative kidney weights


No abnormalities were detected in: pancreas, stomach, small intestine, large intestine, thyroid, parathyroid, spleen, lymph node, bone marrow or brain, 1/6 males of the 800 mg/kg bw group + 14 d recovery showed a moderate effect on the testis (atrophy, seminiferous tubule, diffuse).


 


Females


25,80 mg/kg bw: no adverse effects (decrease of GPT* at 80 mg/kg bw)


250 mg/kg bw: Suppresion of food consumption and body weight gain


800 mg/kg bw: Clinical signs:signs of loss of general conditions like piloerection and soiled fur;


Supression of food consumption and body weight gain; hematology findings: decrease in the hematocrit value, reticulocyte count and platelet count; reduced chlorid levels, calcium elevated and sodium reduced.


Necropsy: cecum was distended;increase in relative kidney weights


No abnormalities were detected: heart, pancreas, stomach, small intestine, large intestine, urinary bladder, ovary, pituitary, thyroid, parathyroid, spleen, lymph node, bone marrow or brain


 


Remarks: Histopathological changes in the kidney tended to recover and the other changes related to the test substance disappeared after 14 -day recovery period.


 


The authors consider: NOAEL: 80 mg/kg bw/day for both sexes


 


*GPT: serum glutamic pyruvic transaminase (synonym: alanine aminotransferase ALAT).

Applicant's summary and conclusion

Conclusions:
No relevant systemic toxic effects were observed in male and female rats after repeated oral administration of 80 mg/kg bw and day CBS. A NOAEL of 80 mg/kg bw/day was assigned for both sexes based on signs of a coagulopathy and adverse effects in the kidney of male rats, suppression of food consumption and body weight gain in female rats (MHWJ 1997).
Executive summary:

Study design


The test substance CBS was evaluated in a subacute gavage study with Crj: CD (SD) rats, which was performed mostly in accordance to regulation requirements (mostly according to OECD TG 407) (MHWJ 1997). Male and female rats (6 per dose and sex) were administered with 0, 25, 80, 250 and 800 mg/kg bw/day for 28 days and were scarified on day 29. Another control and 800 mg/kg bw/day group were treated for 28 days and then kept for a recovery period of 14 days before sacrifice on day 43. In this study data on haematology, clinical biochemistry, organ weights and incidences of histopathological findings were provided.


 


Results


No mortality occurred during the study period. After administration of 800 mg/kg bw/day signs associated with loss of general condition like piloerection and solid fur were observed in female rats. Suppression of food consumption and body weight gain was observed in females given ≥250 mg/kg bw/day (significant p=0.01 at 800 mg/kg bw/day) and in males at 800 mg/kg bw/day.


Hematology revealed statistically significant shortening of the prothrombin time in males given = 250 mg/kg bw/day, and statistically significant decrease in hematocrit value, reticulocyte count and platelet count for the 800 mg/kg bw/day females.


Clinical biochemistry revealed statistically significant decreases in alanine aminotransferase (ALAT) for males of all CBS treated groups and for females given ≥ 80 mg/kg bw/day, in total protein for males treated at ≥ 250 mg/kg bw and day, in chloride levels in males and females at 800 mg/kg bw and day and in sodium levels in females at 800 mg/kg bw/day. In addition, calcium concentration was elevated in females at the 800 mg/kg bw/day dose group.


Urinalysis revealed an increase of ketone bodies in males ≥ 250 mg/kg bw/day.


The statistically significant increase in relative kidney weights in the 800 mg/kg bw/day in males was considered to be associated with an increase in deposition of hyaline droplets in the proximal tubular epithelium of the kidneys in male rats evident at 250 and 800 mg/kg bw/day. This effect in male kidney showed a clear tendency towards reversibility. All other changes were completely reversible after the 14 day recovery period.


 


Conclusion


In summary, CBS-related effects were present in male and females Crj: CD (SD) rats at = 250 mg/kg bw/day. There were signs of coagulopathy of the blood in both sexes and effects in the kidney of male rats. No relevant systemic toxic effects were observed in male and female rats after repeated oral administration of 80 mg/kg bw and day CBS. Based on these findings, the author considered a NOAEL of 80 mg/kg bw/day appropriate for both sexes (MHWJ 1997).