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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Remarks:
Type of genotoxicity: DNA damage and/or repair
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline study with acceptable restrictions.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
In vivo short-term assays for tumor initiation and promotion in the glandular stomach of Fischer rats
Author:
Furihata C. and T. Matsushima
Year:
1995
Bibliographic source:
Mutat. Res. 339, 15-35
Reference Type:
publication
Title:
Induction of ornithine decarboxylase and DNA synthesis in rat stomach mucosa by methylglyoxal
Author:
Furihata, C. et al.
Year:
1985
Bibliographic source:
Carcinogenesis 6 (1), 91-94
Reference Type:
publication
Title:
Mutagens and Carcinogens in Foods
Author:
Furihata, C. and Matsushima, T.
Year:
1986
Bibliographic source:
Ann. Rev. Nutr. 6, 67-94
Reference Type:
publication
Title:
Use of In Vivo / In Vitro Unscheduled DNA Synthesis for Identification of Organ Specific Carcinogens
Author:
Furihata, C. and Matsushima, T.
Year:
1987
Bibliographic source:
CRC Crit. Rev. Toxicol. 17 (3), 245-277
Reference Type:
publication
Title:
Prediction of Possible Carcinogens, Tumor-Promoters and Anti-Tumor Promoters in the Glandular Stomach
Author:
Furihata, C. and Matsushima, T.
Year:
1989
Bibliographic source:
Environ. Mol. Mut. 14, Suppl. 15, 63, Abstract Nr. 178
Reference Type:
publication
Title:
Prediction of Environmental Stomach Carcinogens and Promoters by In Vivo Short-Term Assay
Author:
Furihata, C. and Matsushima, T.
Year:
1987
Bibliographic source:
Environ. Mol. Mut. 9, Suppl. 8, 37, Abstract Nr. 92

Materials and methods

Principles of method if other than guideline:
Method: Determination of unscheduled DNA-synthesis (similar to OECD Guideline 486), ornithindecarboxylase activity, DNA-synthesis, DNA strand breaks and the number of S-phase cells in glandular stomach mucosa cells (Furihata, C. et al.: J. Natl. Cancer Inst. 72, 1327-1334 (1984))
GLP compliance:
not specified
Type of assay:
unscheduled DNA synthesis

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Source: Nakarai Chemicals Ltd ., Kyoto, Japan)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc., Kanagawa, Japan
- Age at study initiation: 8 weeks

Administration / exposure

Route of administration:
other: stomach tube, oral gavage
Vehicle:
- Vehicle(s)/solvent(s) used: water for Methylglyoxal, DMSO for pos. control
- Amount of vehicle: 0.5 mL
Details on exposure:
Animals were not fasted, but given a limited amount of diet (4 g of commercial pellet diet per rat of 200 g body weight) overnight to reduce their stomach contents. The following day they were treated either with 0.5 mL of test item in water or positive control item in DMSO.
Duration of treatment / exposure:
ODC activity (time dep.; 500 mg / kg bw): evaluated 4, 8, 16, 24, 48 and 72h post administration
ODC activity (dose dep.; 16h post admin.): evaluated at 0, 50, 200, 400 and 600 mg / kg bw
DNA synthesis (time dep.; 300 mg / kg bw): evaluated 4, 7, 16, 24, 48 and 72h post administration
DNA synthesis (dose dep.; 16h post admin.): evaluated at 0, 100, 200 and 300 mg / kg bw
DNA synthesis (dose dep.; 4h post admin.): evaluated at 0, 100, 300 and 500 mg / kg bw
S-Phase cells quantification (16h post admin. of 300 mg / kg bw)
Frequency of treatment:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 100, 200, 300, 400, 600 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
five rats per sex per dose / time point (pooled)
Control animals:
yes, concurrent vehicle
Positive control(s):
- N-methyl-N'-nitro-N- nitrosoguanidine (MNNG, Aldrich Chemical Co., Milwaukee, WI, USA)
- Justification for choice of positive control: known glandular stomach carcinogen
- Route of administration: orally (gastric tube)
- Vehicle: DMSO

Examinations

Tissues and cell types examined:
Glandular stomach mucosa

Results and discussion

Test results
Sex:
male
Genotoxicity:
positive
Toxicity:
not specified
Vehicle controls valid:
yes
Negative controls valid:
not applicable
Positive controls valid:
yes

Any other information on results incl. tables

Ornithindecarboxylase activity, DNA-synthesis, unscheduled DNA-synthesis, DNA strand breaks and the number of S-phase cells were determined in the glandular stomach mucosa. All parameters were markedly raised between 300 to 600 mg / kg. Pyruvaldehyde led to a dose-dependent rise of UDS within 16 h and induced ornithine decarboxylase (OCD) activity by 100-fold within 7 h in the glandular stomach mucosa. DNA synthesis returned to the original rate within 24 h post-treatment. The authors discuss Methylglyoxal as a possible tumour promotor and would not exclude a tumour initiating action in the glandular stomach. comparison to the control.

Applicant's summary and conclusion