Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Remarks:
subacute oral toxicity study
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: subacute oral toxicity study (weight of sex organs, and histological examination of the testis documented)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: Guidelines for 28-day repeated dose toxicity testing of chemicals (Japan)
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. At termination of the study weight of organs ovaries, testis, epididymis were determined, and a and histological examination of the testis and epidididymis conducted.
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity: 98.8 %
Specific details on test material used for the study:
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
Details on exposure:
Exposure period: 28 days
Duration of treatment / exposure:
Exposure period: 28 days.
Frequency of treatment:
Daily.
Duration of test:
28 days with a recovery period of 14 days.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control
Dose / conc.:
25 mg/kg bw/day
Dose / conc.:
80 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
800 mg/kg bw/day
No. of animals per sex per dose:
6 per dose and sex
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effects on testis, but dose range with systemic adverse effects (signs of a coagulopathy, adverse effects in the kidney
Dose descriptor:
LOAEL
Effect level:
800 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: increase of the relative testis weights, 1/6 moderate diffuse atrophy of the seminiferous tubule, a slight diffusse interstitial cell hyperplasia and a market decreased sperm content on the epididymis
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remarks'
Remarks on result:
other:
Remarks:
No substance-related effects on absolute and relative ovary weights, no abnormalities were detected in ovary from animals of 800 mg/kg groups, but dose range with systemic adverse effects (e.g. signs of a coagulopathy, reduced body weight gain, reduced food consumption)

Any other information on results incl. tables

All animals survived until the end of the study. Body weight gain and food consumption were reduced in females of the 250  and 800 mg/kg-groups and in males of the 800 mg/kg-group Clinical signs: Deterioration of general condition (piloerection, soiled fur) in females  of the 800 mg/kg-group (for more details see chapter repeated dose toxicity: oral  Relative organ weights of ovary and epididymis were comparable to the control; the testis weight was increased in males of the 800 mg/kg-group (P < 0.01). In one male of the 800 mg/kg/recovery group each there was  observed a moderate diffuse atrophy of the seminiferous tubule, a slight diffuse interstitial cell hyperplasia and a marked decreased sperm content in the epididymis. In the ovary there were no substance-related effects seen.

Histopathological findings in male rats

Organ  Findings  Grade  Dose (mg/kg bw and day)         
     

 after administration period   

 after recovery period   
 Testis      0  800  0  800
   Atrophy, seminiferous tubule, diffuse

++ 

 0/6  0/6  0/6  1/6
   Hyperplasia, interstitial cell, diffuse  +  0/6  0/6  0/6  1/6
   Epididymis: decreased sperm  +++  0/6  0/6  0/6  1/6

+: slight, ++: moderate, +++: market  

The NOAEL for males concerning adverse effects on the reproductive organs   was 250 mg/kg bw/day; the NOAEL for females concerning adverse effects on the reproductive organs was 800 mg/kg bw/day (highest dose tested).

Applicant's summary and conclusion

Executive summary:

In a subacute gavage study groups of Crj:CD (SD) rats were treated with 0, 25, 80, 250 and 800 mg/kg bw and day CBS (MHWJ 1997). No treatment related changes in absolute and relative weights of ovaries and absolute weights of testis were observed. Relative weights of testis were significant higher in animals treated with 800 mg/kg bw and day than in control animals concomitant to decrease body weights. In the recovery group in one out of 6 rats histopathological changes were seen after a 14 day recovery period at 800 mg/kg bw and day (moderate diffuse atrophy of seminiferous tubuli, slight diffuse interstitial cell hyperplasia and market decreased sperm content on the epididymis). No such effects were observed in male terminated immediately after the administration period. No histopathological abnormalities were detected in ovary from females of 800 mg/kg groups.