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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:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
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/day.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 / concentrations
Remarks:
Doses / Concentrations:
25; 80; 250; 800 mg/kg bw/day
Basis:

No. of animals per sex per dose:
Six per dose and sex.
Control animals:
yes, concurrent vehicle
Details on study design:
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 siled fur were observed in females of the 800 mg/kg 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 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 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-groups.  
Decreased hematocrit, reticulocyte count and platelet count in females of  the 800 mg/kg-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-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-group.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Increase of ketone bodies in males of 250 and 800 mg/kg-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-group. Increased relative kidney weights in males and females of the 800 mg/kg-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-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: no adverse effects
Key result
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: signs of a coagulopathy and adverse effects in the kidney of male rats, suppression of food consumption and body weight gain in female rats

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes

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. Based on these findings, the author considered a NOAEL of 80 mg/kg bw and day for both sexes (MHWJ 1997).
Executive summary:

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. No mortality occurred during the study period. After administration of 800 mg/kg bw and day signs of loss of general conditions 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 and day and in males at 800 mg/kg bw and day. Hematology revealed statistically significant shortening of the prothrombin time in males given = 250 mg/kg bw and day, and statistically significant decrease in hematocrit value, reticulocyte count and platelet count for the 800 mg/kg bw and 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 and 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 and day. In addition, calcium concentration was elevated in females at the 800 mg/kg bw and day dose group. Urinalysis revealed an increase of ketone bodies in males treated with = 250 mg/kg bw and day. The statistically significant increase in relative kidney weights in the 800 mg/kg bw and day 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 and day. This effect in male kidney showed a clear tendency towards reversibility. All other changes were completely reversible after the 14 day recovery period. In summary, CBS-related effects were present in male and females Crj: CD (SD) rats at = 250 mg/kg bw and 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 and day for both sexes (MHWJ 1997).