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Description of key information

No guideline compatible repeated dose study or a study with broad toxicological background is available. Instead, data from four publications (for details see discussion) were considered, but were insufficient to characterize repeated dose endpoints of the substance.
In accordance with the REACH legislation only the available data have to be presented. A specific study is not required (Article 18 or Annex VII).

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

The study of Ankrah & Appiah-Opong (1999) aimed to elucidate effects of low levels of pyruvaldehyde on the GSH status, selected GSH dependent functions, and on tolerance to glucose. Dosed mice were allowed to mate and deliver. However, effects on the offspring were not documented. Gross pathohology was carried out, but histopathology was not performed. In conclusion, the study was to a large extend insufficient (test design, dosing period, and dose of the test substance) concerning the assessment of repeated dose toxicity and the results very likely characterize effects at a rather high dosage instead of the intended "very low" doses.

Golej (1998) studied diabetic long-term effects, more specific pathological changes in connective tissue. The influence of pyruvaldehyde, a key intermediate that regularly accumulates in tissues of diabetic patients, on the structure and contents of rat-kidney collagen as well as on morphology of the tissue is considered under long-term feeding (5 months) of the substance at a dose of 50 mg/kg bw/d in drinking water, using 10 animals per group. The thickness of the glomerular basement membrane (electron microscopy) and total kidney collagen were significantly increased when compared with untreated controls. Reduced pepsin-extractability and elevated protein fluorescence suggest that the underlying mechanism may be a decreased collagen solubility induced by pyruvaldehyde-mediated, increased cross-linking. According to the authors, the involvement of pyruvaldehyde in the development of late diabetic complications is supported by these observations.

Designed as dose-range (MTD) finders for anti tumour-studies in mice, the repeated dose data from two studies (Apple & Greenberg 1967; Conroy 1979) had some significant limitations that deteriorated with their insufficient documentation. Whether both genders were tested cannot be assessed. Both setups are not compliant to current test guideline requirements, e.g. with respect to the number of animals per dose group, the dose levels, the duration of exposure (5 or 6 days) and both did not consider systemic toxicity. The MTDs in the Apple & Greenberg study were determined at: 1100 mg/kg (oral); 300 mg/kg (i.m.); ca. 90 mg/kg (i.p).

References

Ankrah, N & Appiah-Opong, R, 1999. Toxicity of low levels of inethylglyoxal: depletion of blood glutathione and adverse effect on glucose tolerance in mice. Toxicol. Lett., 109, 61-67

Golej, J et al., 1998. Oral Administration of Methylglyoxal Leads to Kidney Collagen Accumulation in the Mouse. Life Sciences, 63, 801-807

Apple, MA und Greenberg, DM, 1967. Arrest of Cancer in Mice by Therapy with Normal Metabolites:2-Oxopropanal (NSC-79019) Cancer Chemotherapy Reports 51 (7), 455-464

Conroy, P.J., 1979. Carcinostatic activity of inethylglyoxal in tumour-bearing mice. CIBA Found. Symp. 67, Iss. Submol. Biol. Cancer, 271-300

Justification for classification or non-classification

Based on the available repeated dose data, a justification for a classification of the test item is not possible.