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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and OECD Guideline study
Reason / purpose for cross-reference:
reference to same study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
other: 96/54/EG, B.7 (1996); OECD 407 (1995)
according to guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Hill formula: C36H40N2S6 CAS formula: C36H40N2S6
Details on test material:
Purity: 99.66 %

Test animals

Details on test animals or test system and environmental conditions:
- Source: Harlan Winkelmann GmbH
- Age at study initiation: 5 to 6 weeks
- Fasting period before study:
- Housing:animals were housedindividually in type II A-cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 d

- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 5%
- Air changes (per hr): 15 to 20 changes per hour
- Photoperiod: 12hrs dark / 12hrs light)

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on oral exposure:
Method of administration:
the test substance was administered by gavage from the start of the study until day 27 for the recovery groups and until the day before scheduled sacrifice for the main group.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
during the study period, the test substance content in the vehicle was checked two times, determination of the test substance solved in corn oil was done by HPLC, homogeneity tested prior study and during study
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrations
Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw

No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 40 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 40 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
Main group: 0, 40, 200, 1000 mg/kg, 5 animals/dose/sex
Recovery group (14 d recovery period): 0, 1000 mg/kg 5 animals/dose group
Positive control:


Observations and examinations performed and frequency:
Inspection for morbidity, mortality and general clinical examinations: once a day; body surfaces and orifices, posture, general behavior, breathing and excretory products were assessed
Body weight determination: before the beginning of the study and weekly during the study, feed intake: once per week;
Sacrifice and pathology:
Other examinations:
Hematological investigations, clinical chemistry, neurotoxicity tests (functional observation battery, motor activity)
Dunnett test, p value adjusted Welch test, Kruskal-Wallis test, Mann-Whitney.Wilcoxon test (U tests)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
HAEMATOLOGY: The examination of the red blood cells, thrombocyte counts and prothrombin time showed no toxicologically relevant changes. A statistically significant decrease in erythrocyte counts was seen in high-dose males of the main group treated with the test substance. Hematocrit was unaffected in that group leading to a corresponding increase in mean corpusular volume of single erythrocyte. These changes were only slight and ranged within the 2s limits of historical controls. Furthermore the mean of the concurrent control group was somewhat above the mean male historical controls. No effects were observed in the other sex. Therefore, these changes are considered to be incidental findings of no biologic significance and are unrelated to treatment.

Effect levels

open allclose all
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Clinical observations: No mortality occurred during the study period.

There were no changes in clinical appearance, functional observations, body weights, and food consumption

The functional observations showed no signs or symptoms indicating evidence for systemic toxic and neurotoxic potential. Grip strength and motor activity measurements exhibited no treatment-related changes in both sexes at doses of 1000 mg/kg bw/d and below.

Laboratory findings: There were no biological significant effects of treatment on hematological and biochemical parameters. For a small number of parameters the differences between control and test groups attained a degree of statistical significance. However, the differences were small, not dose-related and inconsistent between the sexes.

Effects in organs: There were no treatment-related findings in organ weights, gross or microscopic pathology in rats of both sexes given 1000 mg/kg bw/d and below. Histopathological changes seen were of a minor nature and at a similar level to those seen in the controls.

Applicant's summary and conclusion

Executive summary:

In a subacute toxicity study the test substance Vulcuren Trial Product KA 9188 was administered orally via gavage to male and female Wistar rats at target concentrations of 0, 40, 200 and 1000 mg/kg body weight for about 4 weeks. In parallel male and female rats (5 per sex and group) were treated with 0 and 1000 mg/kg body weight. These rats were observed for reversibility, continuance or delay occurrence of toxic effects during a recovery period of about 2 weeks. No differences regarding the survival rat or general behaviour were noted compared to the untreated animals. In addition, no relevant differences were observed in mean feed intake and weight gain in any of the treatment groups evaluated compared to the negative control. No neuronal behavior effects were noted in any of the treatment groups. There were no toxicologically relevant changes in haematology and clinical chemistry in animals treated with the test compound. No biologically relevant effects on the organ weights were found in any of the rats treated with the test substance compared to the control animals. In addition, there was no evidence of any gross pathological and histopathological findings associated to dosing with the test compound up to the highest dose group (1000 mg/kg body weight) in both genders. The author concluded that the administration of Vulcuren Trial Product KA 9188 to male and female Wistar rats for about 4 weeks was tolerated without adverse effects up to and including 1000 mg/kg. No delayed occurrence of toxic effects was observed during a recovery period of about 2 weeks (Bayer AG 2000d).