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Key value for chemical safety assessment

Additional information

Genetic toxicity

In Vitro Studies

In a study sponsored by the NTP, butyraldehyde was negative in the Salmonella/mammalian microsome mutagenicity assay when evaluated as a coded chemical in two test laboratories (Mortelmans et al. 1986; Dillon et al. 1988): It was tested in five tester strains (TA97, TA98, TA100, TA1535, TA1537) using the pre-incubation assay with a minimum of five non-toxic concentrations ranging from 33 to 3333 µg/plate, in the presence and absence of Arochlor-induced rat and hamster liver S-9 metabolic activation. Sasaki and Endo (1978) also reported negative mutagenicity results in Salmonella tester strains TA98 and TA100 in a pre-incubation assay with and without rat S-9 metabolic activation. The dose range tested was not reported.

When tested in Chinese hamster ovary (CHO) cells, butryaldehyde did not increase the incidence of chromosomal aberrations at concentrations ranging from 59 to135 µg/ml with and without rat S-9 activation (Galloway et al 1987).  In addition, butyraldehyde was negative for sister chromatid exchange in human lymphocytes when tested in the absence of metabolic activation (Obe and Beek 1979).

Butyraldehyde was positive for induction of sister chromatid exchange in CHO cells when tested in the presence and absence of metabolic activation at nontoxic doses ranging from 9 to 90 µg/ml (Galloway et al 1987). 

There was an increase in the incidence of mutations at the HGPRT and Na/K ATPase loci in Chinese hamster V79 cells exposed to butyraldehyde at concentrations up to 648 µg/ml in the absence of metabolic activation (Brambilla et al. 1989). In studies utilizing primary rat and human hepatocytes, exposure to butyraldehyde at concentrations up to 2163 µg/ml did not result in an increase in DNA repair (Martelli et al. 1994). BASF (1999) reported a negative result when testing the structurally related isobutyraldehyde in the CHO cell HPRT forward mutation assay with and without metabolic activation under GLP conditions (OECD guideline 476),detailed information can be found in the isobutyraldehyde CAS 78-84-2 dossier.

In Vivo Studies: Evaluation negative

Moutschen-Dahmen et al (1975, 1976) reported that male Q strain mice displayed mortality (LD50 was 1140 mg/kg, i.p.), and evidence of cell degeneration, polyploidy during spermatogenesis, and chromosomal aberrations and modifications in sperm morphology when injected intraperitoneally (i.p.) with a single dose of 1 mg per animal (approximate dose 30 mg/kg) or exposed to the chemical in drinking water ( 2 g/L) for 50 days (total dose 15 g/kg or about 300 mg/kg bw/d)]. Meiotic anomalies consisting of degenerative nuclei, multispindle cells, and polyploidy were observed at all stages of spermatogenesis in exposed mice. This test series is considered unreliable due to severe deficiencies in methodology and in documentation.

A micronucleus assay in mice reportedly gave no evidence of clastogenic/genotoxic activity of butyraldehyde (NTP Testing Status 2007). Butyraldehyde was negative when tested in the sex-linked recessive lethal test in Drosophilia (SLRL). Male flies were injected with 10,000 ppm butyraldehyde or fed butyraldehyde in a 0.7% sucrose solution (Valencia et al. 1985).

Genetic toxicity studies

Test

Test System

Result

Reference

Evaluation

In-Vitro Assays

Ames

S. typh. (strains TA100, TA1535, TA1537, TA-98) (TA 100, TA 102, TA 104)

Negative with and without metabolic activation

Mortelmans et al. 1986;

Dillon et al. 1988

Rel 2

Ames

S. typh. (strains TA98; TA100,  TA1535, TA1537, TA1538)

Negative with and without S9

Litton Bionetics 1978

Rel 3 (identity)

Ames

S. typh. (strains TA98; TA100, TA1535, TA1537)

Negative with and without metabolic activation

Florin et al., 1980

Rel 3 (too low dose)

Ames

S. typh. (strains TA98; TA100)

Negative with and without metabolic activation

Sasaki and Endo 1978

Rel 4 (not available)

Gene mutations (mammalian cell)

HGPRT locus, Na/K locus, Chinese hamster lung fibroblasts (V79) in vitro

Positive without metabolic activation

Brambilla et al. 1989

Rel 4 (secondary source)

Chromosomal

aberrations

Chinese hamster ovary cells; in vitro

negative with and without metabolic activation

Galloway et al. 1987 (see also NTP Testing Status)

Rel 4 (secondary source)

Sister chromatid exchanges

Chinese hamster ovary cells; in vitro

Positive with and without metabolic activation

Galloway et al. 1987 (see also NTP Testing Status)

Rel 4 (secondary source)

Sister chromatid exchanges

Chinese hamster ovary cells; in vitro

Negative without metabolic activation

Obe and Beek

Rel 3 (secondary source, deficiencies)

DNA repair

Primary hepatocyrte culture (rat + human)

Negative

Martelli et al. 1994

Rel 4 (secondary source)

In-Vivo Assays

Chromosomal

aberrations

Mouse, male, spermatogenesis, in vivo, i.p., single dose

Positive

Moutschen- Dahmen et al. 1975, 1976

Rel 3 (secondary literature)

Chromosomal

aberrations

Mouse, male, spermatogenesis, in vivo, drinking water,
50 d

Positive

Moutschen-Dahmen et al. 1976

Rel 3 (secondary literature)

Erythrocyte

micronucleus

assay

Mouse, bone marrow; in vivo

Negative

NTP Testing Status

Rel 2 (secondary source, not availalable yet)

Gene mutations SLRL

Drosophila melanogaster; in vivo (oral + injection)

Negative

Valencia et al. 1985 (see also NTP Testing Status)

Rel 2 (secondary source)



Short description of key information:
The genotoxicity of the substance has been evaluated in an appropriate battery of studies in vitro and in vivo. Negative results are reported for bacterial reverse mutation in two Ames tests. Negative results are also reported for investigations of chromosomal aberration and SCE in mammalian cells in vitro, however positive results are reported in an additional study of SCE and also in an HPRT assay. USD assays in primary rat and human hepatocytes report negative results. In vivo, published studies in Drosophila report positive results; these are in contrast to negative results in a high quality (NTP) SLRL study. A further NTP study reports a negative result for the induction of micronuclei in mouse bone marrow. The weight of evidence therefore suggests that the substance in not genotoxic in vivo in mammalian systems

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The genotoxicity of the substance has been evaluated in an appropriate battery of studies in vitro and in vivo. Negative results are reported for bacterial reverse mutation in two Ames tests. Negative results are also reported for investigations of chromosomal aberration and SCE in mammalian cells in vitro, however positive results are reported in an additional study of SCE and also in an HPRT assay. USD assays in primary rat and human hepatocytes report negative results. In vivo, published studies in Drosophila report positive results; these are in contrast to negative results in a high quality (NTP) SLRL study. A further NTP study reports a negative result for the induction of micronuclei in mouse bone marrow. The weight of evidence therefore suggests that the substance is not genotoxic in vivo in mammalian systems and does not require classification for genetic toxicity according to Directive 67/548/EEC or Regulation 1272/2008/EC (CLP).