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EC number: 221-975-0
CAS number: 3302-10-1
3,5,5 -Trimethylhexanoic acid did not produce mutagenic effects in
bacterial reverse mutation tests (Ames-tests). A reliable study on the
induction of chromosomal aberrations in human lympocyates in vitro
yielded an negative result. No HPRT-gene mutations were induced in a
reliable study in Chinese hamster V79 cells in vitro.
The test substance was not mutagenic in an Ames-test with the Salmonella
typh. strains TA98, TA100, TA1535, TA1537 and TA1538 and E.coli WP2uvrA
in concentrations up to 10000 µg/plate, both with or without metabolic
activation (Hoechst AG, 1988).
The study was performed to investigate the potential of
3,5,5-Trimethylhexanoic acid to induce gene mutations at the HPRT locus
in V79 cells of the Chinese hamster. The assay was performed in two
independent experiments, using two parallel cultures each. The first
experiment was performed with and without liver microsomal activation
and a treatment period of 4 hours in concentrations of 102.5; 205.0,
410.0, 820.0, 1093.3 and 1366.7 µg/mL without metabolic activation and
205.0, 410.0, 820.0, 1230.0 and 1640.0 µg/mL with metabolic activation.
The second experiment was performed with a treatment time of 4
hours with and 24 hours without metabolic activation. The test
conentations were 500.0, 750.0, 1000.0, 1250.0, 1500.0 and 1640.0 µg/mL
without metabolic activation and 750.0, 1000.0, 1250.0, 1500.0 and
1640.0 µg/mL with metabolic activation. The highest concentration in the
main experiments (1640.0 µg/mL) was equal to a molar concentration of
about 10 mM and was adjusted to purity.
No substantial and reproducible dose dependent increase of the
mutation frequency was observed in both main experiments.
Appropriate reference mutagens, used as positive controls, induced
a distinct increase in mutant colonies and thus, showed the sensitivity
of the test item and the activity of the metabolic activation system.
Under the experimental conditions of this study the test item did
not induce gene mutations at the HPRT locus in V79 cells.
Therefore, 3,5,5-Trimethylhexanoic acid is
considered to be non-mutagenic in this HPRT assay (Carboxylic acids
REACH Consortium, 2010). This study was performed according to guideline
EU B17 and OECD 416 and is therefore considered to be of high
For details see attachment
An in vitro mammalian chromosomal aberration test according to OECD TG
473 and GLP has been performed with human lymphocytes.
Duplicate cultures of human lymphocytes, treated with the test item
(vehicle DMSO), were evaluated for chromosome aberrations at up to four
dose levels, together with vehicle and positive controls. In this study,
three exposure conditions were investigated; 4 hours exposure in the
presence of an induced rat liver homogenate metabolizing system (S9), at
a 2% final concentration with cell harvest after a 20-hour expression
period, 4 hours exposure in the absence of metabolic activation (S9)
with a 20-hour expression period and a 24-hour exposure in the absence
of metabolic activation.
The dose levels selected for the main experiment were as follows (up to
the recommenden highest dose level of 10 mM (1580 µg/mL or the dose
level with a tolerable cytotoxicity):
4(20)-hour without S9: 0*, 98.75, 197.5, 395, 790, 987.5*, 1185*, 1580*
4(20)-hour with S9 (2%): 0*, 98.75, 197.5, 395, 790*, 987.5*, 1185*,
24-hour without S9: 0*, 24.69, 49.38, 98.75*, 148.13*, 197.5*, 296.25*,
Dose levels marked with * were selected for analysis of chromosomal
The test item did not induce any statistically significant increases in
the frequency of cells with aberrations, using a dose range that
included a dose level that approached 55±5% mitotic inhibition or was
the maximum recommended dose level, depending on exposure group.
Positive and vehicle controls were valid.
In the absence of information on a species specific activity the effects
are regarded as relevant for humans.
No mutagenic effects of the test substance were observed in 3
reliable studies with bacteria (2 Ames-tests and one study in E.coli;
Hoechst, 1988, key study, RL1; Exxon, 2004, RL2).
In a test on induction of chromosomal aberration in
cultures of human lymphocytes, treated with the test item (vehicle
DMSO), were evaluated for chromosome aberrations after 4 hours exposure
in the presence and absence of an induced rat liver homogenate
metabolizing system (S9) with cell harvest after a 20-hour expression
period (maximum concentration 1580 µg/mL), and a 24-hour exposure in the
absence of metabolic activation (maximum concentration 395 µg/mL). The
test item did not induce any statistically significant increases in the
frequency of cells with aberrations, using a dose range that included a
dose level that approached 55±5% mitotic inhibition or was the maximum
recommended dose level, depending on exposure group (Envigo, 2018, RL 1).
In a test on induction of chromosomal aberration in CHO cells in
vitro, the first series of experiments showed no clastogenic effect. In
the repeated experiment, statistically significant differences in the
mean percentage of aberrant cells were evident between the vehicle
control and the 1250 µg/ml dose at the 19 hour harvest with metabolic
activation (+S9) as well as at the 43 hour harvest without metabolic
activation (-S9). However, the effect level was within the acceptable
range for the vehicle control. A significant increase, also exceeding
the historical control range, was observed in the 19 h harvest without
metabolic activation (6.5%), which is a positive response (Exxon, 2004,
RL3). Based on this inconsistent and conflicting data, the test result
is regarded as ambiguous. Because of the inadequate exposure conditions,
more weight is given to the chromosomal aberration study in human
lymphocytes (Envigo, 2018, see above).
The induction of HPRT gene mutations was tested in Chinese hamster
V79 cells. No mutational activity was observed with and without
metabolic activation in this reliable study (Oxea, BASF 2010).
Based on the negative findings in several in vitro studies it is
concluded that 3,5,5 -trimethylhexanoic acid has not to be classified as
genotoxic according to Regulation (EC) No 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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