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Key value for chemical safety assessment

Additional information

Mutagenicity in bacterial cells

No valid study on the genetic toxicity properties of 2-methylbutanal was located. Negative results in the Ames test with and without metabolic activation were reported in two independent publications, but the number of test strains used was low, and the documentation was poor. The reliability of these studies is therefore low (RL4) though the results may be used to demonstrate a lack of genotoxic potential in a weight of evidence approach.

It is known that linear and branched alkyl aldehydes of a comparable chain length were negative in the Ames test, with and without metabolic activation. This was confirmed by the results of a structure-activity analysis using the OECD Toolbox v. 1.1. Starting with data from 1524 aldehydes, refinement ( i.e. elimination of alkenes, arenes, carboxylic acids, alpha-beta unsaturated aldehydes, etc.) resulted in a set of branched and linear monofunctional aldehydes with a carbon chain length of C2 to C9 which were all negative in the Ames test (i.e. -1.00 in the attached plot). A further selection of the five nearest neighbours (C3-C7; brownish dots) to 2-methylbutanal (red dot) were all negative. It is therefore assumed that 2-methylbutanal is not genotoxic in bacteria in vitro.

 

 

Read across: aldehyde mutagenicity and carcinogenicity data

The table below summarises available data on two closely related aldehydes, valeraldehyde, isovaleraldehyde, and isobutyraldehyde which can be used for read across. Structure, chain length, reactivity, physico-chemical properties, and metabolism of these aliphatic aldehydes are very similar, thus justifying cross reading of results from these substances to 2-methylbutyraldehyde.

 

It may be observed that the aldehydes give mostly negative results in the Ames test (bacterial cells), but positive results with mammalian cells in vitro, which is in sharp contrast to the negative results obtained in-vivo using the Mouse Micronucleus Test, or in carcinogenicity assays.

 

Study

Substance

Reliability

GLP

Test type/
Protocol

Guideline

Results

Remarks

In vitro tests;
gene mutation studies in bacteria

NTP
1988

Valeraldehyde

2

no data

Ames

similar
OECD 471

negative

tested up to 2000 µg/plate with and without metab. activ.

In vitro tests,
studies in mammalian cells

Brambilla
1989

Valeraldehyde

2

no

HPRT
gene mutation

similar
OECD 476

positive

V79 cells;
without metabolic activation;
3 concentrations
up to 2580 µg/mL;
cytotoxicity observed

Martelli 1994

Valeraldehyde

2

no

Gen. Tox.
 UDS

similar
OECD 482

positive

primary hepatocytes;
3 concentrations,
up to 2580 µg/mL
cytotoxicity observed

Marinari
1984

Valeraldehyde

2

no

DNA damage
(alkaline elution)

no TG

positive

single strand breaks,
no cross linking

BASF SE
1999

Read across;
Isobutyraldehyde

1

yes

HPRT
gene mutation

according
OECD 476

negative

CHO cells;
with and without metab. activ.;
5 concentrations,
up to 800 µg/mL
cytotoxicity observed with metabolic activation

In vivo tests;
somatic cell studies

BASF AG
2001

Read across;
Isovaleraldehyde

1

yes

MNT

Similar to
OECD 474

negative

Read across;
single ip injection;

3 concentrations up to
100 mg/kg bw (overt toxicity)

NTP
1999

Read across;
Isobutyraldehyde

2

no data

MNT

Similar to
OECD 474

negative

3 repeat single ip injections;
6 concentrations up to
1250 mg/kg bw (single dose)

NTP
1999

Read across;
Isobutyraldehyde

2

no data

Mammalian bone marrow
CA

Similar to
OECD 475

positive

Read across;
single ip injection;

5 concentrations up to
1750 mg/kg bw
significant CA associated with notable clinical signs of toxicity

NTP
1999

Read across
isobutyraldehyde

2

no data

Chronic cancer study

OECD 451

negative

mouse

NTP
1999

Read across
isobutyraldehyde

2

no data

Chronic cancer study

OECD 451

negative

rat

 

 

The Ames test is negative for several other related aldehydes (e.g. isovaleraldehyde, butyraldehyde, isobutyraldehyde, propionaldehyde).

 

Results of in vitro tests with mammalian cell systems are predominantly positive e.g Brambilla (1989). In contrast, the HPRT test for isobutyraldehyde (BASF AG, 1999) was negative.

 

Regarding in vivo genotoxicity, Isovaleraldehyde was tested by BASF in an in vivo mammalian erythrocyte micronucleus test. The result was negative (no increase in polychromatic erythrocytes containing neither small nor large micronuclei). The study satisfies the requirements of OECD TG 474.

 

Further, isobutyraldehyde was thoroughly tested by NTP. A mouse bone marrow micronucleus test was negative, i.e. in two independent tests, there was no significant increase compared to controls of micronucleated polychromatic erythrocytes from animals treated with three repeat doses (24 h interval) of isobutyraldehyde up to the maximum (single) dose of 1250 mg/kg bw. In contrast, in two tests for induction of chromosomal aberrations in mouse bone marrow, results were clearly positive. After intraperitoneal injection of increasing isobutyraldehyde single doses up to a maximum of 1750 mg/kg bw, increasing frequencies of aberrant cells were observed. Significant increases in aberrant cells compared to controls was only seen at doses which caused notable toxicity (1500 and 1750 mg/kg bw). These doses were higher than the maximum single dose administered in the micronucleus test at a single day.

 

Given these conflicting results, NTP decided to perform long-term inhalation cancer studies in rats and mice similar to the OECD test guideline 451 (isobutyraldehyde concentrations 0, 1500, 3000, and 6000 mg/m³). There was no evidence of carcinogenic potential in males or females of either species.

 

 

Based on the above Read Across, it is concluded that 2-methylbutyraldehyde is not genotoxic.

 

 

 


Short description of key information:
2-methylbutyraldehyde is considered to be not genotoxic, based on the results of closely related short chained (C3 - C9) linear and branched alkyl aldehydes that were evaluated using the OECD Toolbox v. 1.1, and a read across approach which included also other endpoints and in-vivo data. Valid data related to the genetic toxicity of 2-methylbutyraldehyde could not be located, but two Ames studies of low reliability (RL4) are in line with the overall result.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No classification required. Classification criteria are not met.