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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and OECD Guideline study

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Qualifier:
according to guideline
Guideline:
other: 92/69/EWG, B.12 (Mikrokerntest)
GLP compliance:
yes
Type of assay:
micronucleus assay

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:
mouse
Strain:
NMRI
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, borchen
- Age at study initiation: 6 to 12 weeks
- Weight at study initiation: 36-41 g
- Housing: animals were kept singly in type I cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at leat 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1.5°C
- Humidity (%): 40% to 70%
- Air changes (per hr):
- Photoperiod: 12hrs dark / 12 hrs light


Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
Maiskeimöl

"ENGLISH"

corn oil
Details on exposure:
Vulcuren Versuchsprodukt KA 9188 was suspended in corn oil using a microdismembrator for 5 minutes, and formed yellowish turbid viscous suspensions. The suspensions were stirred with a magnetic mixer during administration and injected intraperitoneally.
The volume administered was 20 ml/kg bw for treatment group and negative control, 10 ml/kg for the postive control
Duration of treatment / exposure:
Twice
Frequency of treatment:
Twice
Post exposure period:
24 h
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1000, 2000, 4000
Basis:
nominal conc.
No. of animals per sex per dose:
Male: 1000 mg/kg; No. of animals: 5; Sacrifice time: 24 hours
Male: 2000 mg/kg; No. of animals: 5; Sacrifice time: 24 hours
Male: 4000 mg/kg; No. of animals: 5; Sacrifice time: 24 hours
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide (20 mg(kg)

Examinations

Tissues and cell types examined:
Bone marrow from femur
Details of tissue and slide preparation:
DETAILS OF SLIDE PREPARATION: Schmidt's method was used to produce the smear (1975, Mutat. Res., 31, 9-15)
Evaluation criteria:
An assay was considered acceptable if the figures of negative and positive controls were within the expected range, in accordance with the laboratory's experience and/ or available literature data.
Statistics:
Wilcoxon's non-parametric rank sum test

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Remarks:
Doses producing toxicity: >= 1000 mg/kg bw.
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Observations:
Keine Todesfälle; Vergiftungssymptome: u.a. Apathie,
gesträubtes Fell, Krämpfe

"ENGLISH"

No deaths occurred. Toxic effects: apathy, piloerection,
cramps

Any other information on results incl. tables

Clinical observations at 1000 mg/kg and higher:

Apathy, roughened fur, spasm and periodically stretching of body; these symptoms demonstrate relevant systemic exposure of males to Vulcuren Versuchsprodukt KA 9188.

Mortality: no substance induced mortality

Ratio polychromatic (PCE) to normochromatic erythrocytes (NCE):

The ratio of polychromatic to normochromatic erythrocytes in males was not biologically relevant altered by the treatment with Vulcuren Versuchsprodukt KA 9188 compared to the negative control (control: 2000: 1938, 1000 mg/kg: 2000: 1894, 2000 mg/kg: 2000: 2121, 4000 mg/kg: 2000: 2456).

No biologically relevant and statistically significant increase of micronucleated polychromatic erythrocytes was noted in the Vulcuren Versuchsprodukt KA 9188 treated animals compared to the negative control

Incidence of micronucleated PCE:

negative control: 3.0/2000

2 x 1000 mg/kg bw: 2.2

2 x 2000 mg/kg bw: 3.0

2 x 4000 mg/kg bw: 2.4

In addition, no biologically relevant variation between the negative control and the treatment groups were noted in the number of micronucleated normochromatic erythrocytes.

The positive control, CPA, caused a clear increase in the number of polychromatic erythrocytes with micronuclei. The incidence of micronucleated cells was 28.4/2000, which represents biologically relevant increases in comparison to the negative control.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Executive summary:

The test substance Vulcuren VP KA 9188 was evaluated in the in vivo micronucleus assay with male NMRI mice. The test substance was applied at concentrations of 0, 1000, 2000, 4000 mg/kg body weight. All animals from the treatment groups showed clinical signs like apathy, roughened fur, spasm and periodically stretching of the body, which demonstrated a relevant systemic exposure of males to Vulcuren VP KA 9188. The ratio of polychromatic to normochromatic erythrocytes in males was not biologically relevant altered by the treatment with the test substance compared to the negative control. In addition, no biologically relevant and statistically significant increase of micronucleated polychromatic erythrocytes was noted in the treated animals compared to the negative control (Bayer AG 2000c).

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