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In vitro studies: bacterial reverse mutation tests

Pyruvaldehyde was not tested in an Ames assay fully compliant to OECD TG 471, because in all available publications, only a subset of the required bacterial strains were used. Nevertheless, most available tests are based on the principles described by Ames et al. (Mut. Res., 31, 347-364, 1975 and Proc. Nat. Acad. Sci. USA, 70, 782-786, 1973) and the results of all publications as a whole can therefore be considered for a meaningful evaluation of the test substance in a weight of evidence approach.

In this evaluation, all of the 34 study records describing Ames tests unanimously characterized the test substance pyruvaldehyde as genotoxic. Five studies (Barrueco & de la Pena 1988; Hagemann 1988; Herrera & Laborda 1988; Meshram & Rao 1988; Moore 1984) were quoted as exemplary for the employment of the test substance as positive control in Ames tests, commonly for the Salmonella typhimurium TA 104 strain without S9-mix. The remaining publications describe positive results with and without S9-mix from the Escherichia coli (WP-strain) and a wide variety of Salmonella typhimurium strains (TA 97, 98, 100, 102, 104, 1537, 1538, 4001, 4006), although the strains actually used in each assay were in each case limited to a subset. In some assays, not each respective strain tested showed statistically significant positive results (e.g. Nagao 1986, TA 98, 1538) but considering the results from all publications, pyruvaldehyde induced mutations in all strains tested.

In-vitro studies: other bacterial, mammalian cell mutation and genotoxicity tests

None of the available assays were fully compliant to present test guidelines (OECD, EC). Nevertheless most of the tests are based on the principles described in the respective guidelines. Pyruvaldehyde produced positive results in a wide variety of further in vitro test systems, e.g. in chromosome aberration assays (human lymphocytes: Migliore 1990; V79 cells: Nishi 1989), sister chromatid exchange tests (CHO cells: Faggin 1985; CHO AUXB1 cells: Taylor 1985 & Tucker 1989; human lymphocytes: Tucker 1989 & Migliore 1990), a micronucleus test (human lymphocytes: Migliore 1990), HPRT assays (V79 cells: Cajelli 1987; human T-lymphocytes: Hou 1995), DNA damage and repair assays (CHO cells: Brambilla 1985 & Rinkus 1987; human T-lymphocytes: Hou 1995; calf thymus DNA: Rahman 1990; bacteriophage Phi DNA: Morita 1991), the Ara test (forward mutation assay to L-arabinose resistance in S. typhimurium: Ariza 1988), a DTr test (diphteria toxin resistance in CHL cells: Nagao 1986) mitotic gene conversion tests (S. cerevisiae D7: Bronzetti 1987; Nagao 1986), a reverse point mutation test (S. cerevisiae D7: Bronzetti 1987), a SOS chromotest (E. coli & s. typhimurium: Sundermann 1994) and an UMU test (S. typhimurium TA1535/pSK1002: Obana 1993).

In vivo

None of the available assays were fully compliant to present test guidelines (OECD, EC).

Migliore et al. (1990) studied the induction of chromosomal damage in vivo in ileum and duodenum cells of males mice. The animals were fasted for 8 h before mutagenic treatment. An aqueous solution of Methylglyoxal (0.5 mL) corresponding to 400 and 600 mg/kg body wt was administered p.o. (four animals per dose). The positive control was methylhydrazine. For the SCE analysis a tablet of BrdU corresponding to a dose of 25 mg/kg body wt was placed s.c.. The four control mice received the vehicle alone. Two hours before the mice were killed (performed at the 24th h) colchicine (3.5 mg/kg body wt) was administered i .p.. Immediately thereafter tissues were removed and processed. The obtained cell suspension was spread over slides, fixed and stained. Coded slides were analyzed for the presence of chromosomal numerical (hyperploid and polyploid) and structural aberrations in at least 100 well-spread first metaphases. SCEs in 25 second metaphases of good quality were scored. Pyruvaldehyde did not cause chromosome aberration in ileum and duodenum cells, but a very weak and statistically significant increase of sister chromatid exchanges in duodenum cells of mice at 600 mg/kg bw.

Martelli et al. (1989) examined the induction of micronuclei in vivo in hepatocytes and bonemarrow erythrocytes from Sprague-Dawley male albino-rats treated orally with pyruvaldehyde. The animals were randomly divided into six groups of five rats each, and treated as follows: group A, controls; group B, 800 mg/kg of methylglyoxal administered by gavage in a single dose; group C, 400 mg/kg/day of Methylglyoxal, dissolved in drinking water, for 5 successive days; groups D and E; receiving respectively a single i.p. dose of 10 mg/kg DMN and of 0.85 mg/kg MitC, both used as positive controls; group F, two i.p. doses of 0.85 mg/kg MitC at 30 and 6 h before killing. In the rats of groups A, B, D, and E, a 2/3 hepatectomy was performed 20 h before treatment, and liver and bone-marrow cells were isolated 48 h after the administration of the test compound. In the rats of the group C, a 2/3 hepatectomy was carried out 48 h after the last dose, and liver and bone marrow cells were obtained 48 h later. The rats of group F (positive control receiving mitomycin C at 30 and 6 h before killing) were not submitted to partial hepatectomy, and only bone-marrow cells were analyzed. The respective cell suspensions were put on microscope slides, fixed and stained. Micronuclei were scored in intact hepatocytes and polychromatic erythrocytes (micronucleated cells per 1000 polychromatic erythrocytes). In addition percentages of binucleated cells were evaluated in hepatocytes and the ratio of normochromatic to polychromatic erythrocytes in erythrocytes. A weak and statistically significant increase of micronuclei was found only in hepatocytes of rats treated with a single dose (800 mg/kg bw), but not so in repeatedly treated rats at a lower dosage (400 mg/kg bw/d for 5 days). No indications for an induction of micronuclei in erythrocytes were found.

A statistically significant increase of micro-nucleated hepatocytes was detected only in one study in rats treated by oral gavage with the single dose of 800 mg/kg bw, which is close to the LD50 value (LD50 p .o. = 1380 mg/kg) . Since Methylglyoxal is oxidized to lactate by the glyoxalase system and to pyruvate by the alpha-ketoaldehyde dehydrogenase, it can be assumed that the clastogenic effect occurs only when saturation of these enzyme activities is attained. Thus, the absence of a positive response in the liver of rats receiving 400 mg/kg/day in drinking water for five successive days may be reasonably attributed to the markedly lower concentration reached with this dosage schedule.

Pyruvaldehyde was administered to male F344 rats as an aqueous solution at doses between 50 and 600 mg/kg bw by oral gavage. Positive controls received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in DMSO and negative controls the respective vehicle. Rats were killed between 0 and 72 hours after substance administration. Glandular stomach mucosa was removed and examinded for induction of ornithine decarboxylase (ODC) activity, unscheduled DNA synthesis (UDS), DNA synthesis (Furihata et al., 1985). In addition, DNA strand scission (by alkaline elution method) was determined in the glandular stomach mucosa of rats in a further study by Furihata and Matsushima (1989). All parameters were markedly raised between 300 to 600 mg/kg bw. Pyruvaldehyde led to a dose-dependent rise of UDS within 16 h, induced ornithine decarboxylase (OCD) activity by 100-fold within 7 h and DNA-synthesis by 26-fold within 16 h in the glandular stomach mucosa. DNA synthesis and ODC activity returned to the original rate within 24 h and 48 h, respectively. After administration of Methylglyoxal the stomach mucosa was found reddened and partly white in an acute tox. study.

In the case of Methylglyoxal, an irritation of the stomach tissue and cytotoxic effects after application via stomach tube may leed to the observed findings.

Results of the sex linked recessive lethal assays using Drosophila melanogaster (Barnett 1998, Obana 1993) as well as the X-chromosome nondisjunction (ND) test and the heritable (autosomal) translocation assay using the same species (both: Barnett 1998) were negative in all but one case (Barnett 1998: positive in males after intrabdominal injection of 1.7 M, but not when fed); however the results were of limited relevance for the assessment of genotoxicity of pyruvaldehyde.

Short description of key information:
In a variety of in vitro bacterial, yeast and mammalian cell mutagenicity tests (e. g. chromosome aberration, sister chromatid exchange, micronucleus test, HGPRT, DNA damage & repair, Ara test, DTr, mitotic gene conversion/reverse point mutation, SOS test, UMU test), pyruvaldehyde was genotoxic.
Furthermore, weak positive results have been reported in vivo in the 1) sister chromatid exchange in mice (duodenum cells), 2) micronucleus test in rats (hepatocytes), 3) UDS test in rats (glandular stomach mucosa). Thus, pyruvaldehyde is classified for genetic toxicity.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Pyruvaldehyde showed a mutagenic potential in vitro. In in vivo studies, a weak mutagenic potential was observed.

After overall evaluation of the existing data, pyruvaldehyde needs to be classified according to EU chemical legislation and referring to GHS, Annex VI of CLP regulation and Directive 67/548 (GHS cat. 2, R68).