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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: subacute toxicity study according to OECD 407
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: subacute toxicity study done according to OECD Guideline 407
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 407
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
429-280-6
EC Name:
-
Cas Number:
151900-44-6
Molecular formula:
Hill formula: C36H40N2S6 CAS formula: C36H40N2S6
IUPAC Name:
N,N-dibenzyl({6-[(dibenzylcarbamothioyl)disulfanyl]hexyl}disulfanyl)carbothioamide
Details on test material:
Purity: 99.66 %

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH
- Age at study initiation: 5 to 6 weeks
- Fasting period before study:
- Housing:animals were housed individually in type II A-cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 d


ENVIRONMENTAL CONDITIONS
- 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
Vehicle:
corn oil
Details on exposure:
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:
yes
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:
Daily
Details on study schedule:
28 d repeated dose study
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw
Basis:
nominal conc.
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:
none

Examinations

Statistics:
Dunnett test, p value adjusted Welch test, Kruskal-Wallis test, Mann-Whitney.Wilcoxon test (U tests)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Details on results (P0)

histological examinations of sex organs (epididymides, ovaries, oviducts, prostate, testes, uterus with uterine cervix, vagina): no substance-related effects observed

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No effects in organ weights, gross pathology and histology in the sex organs evaluated

Overall reproductive toxicity

Reproductive 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.

No effects in organ weights, gross pathology and histology in the sex organs evaluated (epididymides, ovaries, oviducts, prostate, testes, uterus with uterine cervix, vagina)

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 behavior 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.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. In addition, no substance-related effects were noted in the evaluated sex organs. 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).