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EC number: 202-436-9
CAS number: 95-63-6
Carcinogenicity tests have not been conducted on 1,2,4-trimethylbenzene or other trimethylbenzene isomers but there are sufficient data to indicate that they do not pose a significant carcinogenic hazard to humans. Trimethylbenzenes have been shown to have no significant genotoxic activity in vitro and in vivo. There are no data from toxicokinetics, metabolism and distribution findings to indicate any target for possible genotoxic carcinogenic activity. The cellular changes arising from repeated administration of trimethylbenzenes to animals are also minimal.
1,2,4-Trimethylbenzene has a low potential
for carcinogenicity and therefore does not warrant classification under
DSD or CLP.
This endpoint summary provides an
evaluation covering the range of trimethylbenzene materials including
1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene and
There are no lifetime animal studies
available on trimethylbenzene in order to directly investigate for
possible carcinogenic activity. However, there is sufficient information
available to make a satisfactory assessment of the likely carcinogenic
potential of the material.
a) Non-testing information relevant
Trimethylbenzene is a simple aliphatic
structure. It contains no centres of chemical functional activity and
contains no alerts for possible genotoxic activity when considered
against the criteria established by Ashby and Tennant (1988). The
chemical would therefore not be expected to show any significant
genotoxic activity in vitro or in vivo, and therefore would also not be
expected to show carcinogenic activity due to a genotoxic mechanism.
The metabolism and disposition of
1,2,4-trimethylbenzene and 1,3,5-trimethylbenzene have been examined in
animals and are quite similar. Both materials form dimethylhippuric acid
in rats administered a single oral dose. Inhalation toxicokinetic
studies in humans show similar elimination kinetics and metabolism. The
major route of metabolism is therefore through oxidation and subsequent
conjugation of the methyl groups. None of these chemicals carry any
alerts for possible genotoxic activity when considered as above.
Trimethylbenzenes are therefore
relatively simple aromatic chemicals, which, when evaluated using
accepted structure activity relationship considerations, have no alerts
for significant genotoxicity or subsequent carcinogenic activity.
b) Testing data relevant for
In vitro data
Trimethylbenzene isomers have been
examined for mutagenicity in vitro in a range of recognised core
assay types, including in bacteria (Ames test for gene mutation), and in
mammalian cells (gene mutation, chromosomal damage and sister chromatid
exchange endpoints). Negative results were obtained in all assays,
except for 1,2,3-trimethylbenzene, which gave a positive response in
bacteria only, and then only in the absence of a mammalian metabolising
system. In the presence of a mammalian metabolising system it gave a
negative response. Overall, it is concluded that the data do not
indicate any significant genotoxic activity for 1,2,4-trimethylbenzene.
a) Genotoxicity studies
isomers have been examined in the mouse bone marrow micronucleus assay,
and were found not to be mutagenic. This
is an established core assay for the evaluation of mutagenicity in vivo
and indicative of no mutagenic activity in animals. In
contrast, the reporting of data in the same study for the endpoint of
sister chromatid exchange is not considered to be an observation of such
weight in an evaluation of mutagenicity. The
observation of small increases in sister chromatid exchange in the mouse
for the high flash naptha (containing 55% trimethylbenzene isomers) is
therefore not considered to indicate a significant genotoxic effect,
since the increases were small, and the endpoint is one of uncertain
b) Toxicity studies
A number of repeat dose toxicity
studies in animals of up to 90 days duration are available using TMB
isomers or mixtures containing TMB isomers. Studies have been undertaken
using both the oral (gavage) and inhalation routes.
1,2,3 -Trimethylbenzene and
1,2,4-trimethylbenzene were examined in 28 day oral gavage studies in
rats at doses up to 1000 mg/kg/day. For 1,2,3-trimethylbenzene,
increases in liver and kidney weights were observed together with
decreased thymus weights, clinical chemistry changes and at the top dose
only, hyaline droplets and eosinophilic changes in the kidneys of male
animals. For 1,2,4-trimethylbenzene, increases in liver and kidney
weights were again observed, but no haematological changes or
abnormalities at necropsy. A 90 day oral gavage study in rats was
conducted with 1,3,5-trimethylbenzene, at doses up to 600 mg/kg/day,
including a recovery group terminated after a further 28 day period. The
changes reported were increased liver weights, increased kidney weights
(males only), and increases serum phosphorus levels. No microscopic
changes related to treatment were observed in the liver, kidney or other
organs. No effects were observed in animals at the end of the 28 day
recovery period, and all of the effects seen after 90 days were
considered adaptive changes.
1,2,3 -Trimethylbenzene administered
to rats by inhalation at dose levels up to 1230 mg/m3 for 6h/day, 5
days/week for 90 days resulted in increased liver weights in males and
some limited clinical chemistry changes in both sexes. Rats were exposed
to 1,2,4-trimethylbenzene by inhalation at dose levels up to 1250 mg/m3
for 6h/day, 5 days/week for 90 days, and no toxicologically significant
changes were reported. A second 90 day inhalation study in the rat
reported only minimal clinical chemistry changes that were considered to
be adaptive in nature. 1,3,5-trimethylbenzene was administered to rats
by inhalation for 6h/day, 5 days/week for 5 weeks at 3050 mg/m3. Limited
changes in white blood cells were the only effects reported.
Exposure of rats by inhalation to a
C9-C10 fraction from petroleum distillates, containing 74% alkylbenzenes
(Firth, 2008), at a level of 616ppm for 135 days gave rise to congestive
and hemorrhagic changes in lungs, kidneys, spleen and omental
tissue. Inflammatory changes in the lung, and haemorrhages from the
mouth and nose and transitory blood changes were also reported.
Exposure of rats by inhalation for 13
weeks to a 50:50 blend of Shellsol A and Solvesso 100 (a C9-C10 dialkyl
and trialkylbenzene mixture) up to 1800 mg/m3, resulted in increased
liver and kidney weights in males, but no histopathological changes. The
changes were considered adaptive in nature and a NOAEC of 1800 mg/m3 was
The liver and kidney are the two main
organs that showed some changes following exposure to trimethylbenzenes.
In both cases increased liver weights were seen. No histopathological
changes were observed in the liver, and the minimal changes seen at 90
days were reversible after a recovery period of a further 28 days. This
is consistent with a common reaction of the liver to continued exposure
to a chemical that undergoes hepatic metabolism, and is considered an
adaptive change. The only histopathological changes reported in the
kidney on repeated exposure were hyaline droplets and eosinophilic
bodies observed only after 1,2,3-TMB administration. These changes were
only reported in male animals, and are consistent with the formation of
the alpha-2u globulin protein. This is a relatively common response
following exposure of male rats to certain hydrocarbons. The phenomenon
has been well studied and it has been shown that it is a response
specific to male rats, and it is generally agreed that it is an
observation of no relevance to humans (USEPA 1991).
It is possible that the underlying
modes of action causing these changes in the liver and kidney may, on
exposure of appropriate rodents to high levels of TMBs for the duration
of a lifetime, result in an increase in tumours in the liver and
kidney. Any tumours in the kidney would be expected in male rats
only. If such tumours were observed, they would be considered to have
arisen by established and accepted non-genotoxic modes of action, and
would be appropriate for assessment by using standard toxicological
assessment, and not by any assessment for genotoxic carcinogenicity. Any
kidney tumours that may be induced would be expected to be in male rats
and due to a mechanism involving alpha-2u globulin protein and would be
considered to have no relevance for humans.
The other various changes in clinical
chemistry or blood parameters are not considered to indicate changes or
mechanisms likely to induce tumours on chronic exposure.
Various trimethylbenzene isomers,
either as pure chemicals or as components of mixtures have been examined
in a range of studies of approximately 90 days including both oral and
inhalation routes of exposure. The effects produced have been described
including histopathological evaluation, and including an evaluation
after a recovery period for the 1,3,5-TMB isomer. The effects reported
have been relatively limited and are sufficient to allow an assessment
of the likely effects of chronic exposure to TMBs. It is considered
unlikely that significant new data would be gained by undertaking
specific chronic exposure studies.
The toxicokinetics, metabolism and
distribution findings for 1,2,4-TMB and other isomers in animals
indicate a chemical that is cleared primarily and rapidly through the
urine, and with no accumulation. Metabolism results in oxidation of the
methyl groups and subsequent conjugation.
1,2,4 -Trimethylbenzene and other
trimethylbenzene isomers are simple aromatic chemicals that do not carry
alerts for genotoxic activity. Trimethylbenzenes have been shown to
have no significant genotoxic activity in vitro and in vivo. These
observations indicate that trimethylbenzenes are not expected to be
There are no data from toxicokinetics,
metabolism and distribution findings to indicate any target for possible
genotoxic carcinogenic activity.
A number of trimethylbenzenes have
been examined in repeat dose inhalation studies and shown low toxicity.
The liver and kidney showed changes consistent with an adaptive change
to TMB administration. The modes of action leading to such adaptive
changes are such that any tumours resulting on chronic exposure to TMBs
would not arise though a genotoxic mechanism and would either be of no
relevance to humans (kidney), or of limited relevance (liver), and would
be encompassed by the standard toxicological assessment process.
It is concluded that there are
sufficient data to indicate that trimethylbenzenes do not pose a risk of
genotoxic carcinogenicity. There are also sufficient data to understand
that the cellular changes arising from repeated administration of
trimethylbenzenes to animals are minimal and to conclude that
trimethylbenzenes are unlikely to pose a significant carcinogenic hazard
to humans. The conduct of animal carcinogenicity studies to further
evaluate this is considered to be unwarranted.
Ashby J and Tennant RW (1988) Chemical
structure, Salmonella mutagenicity and extent of
carcinogenicity as indicators of genotoxic carcinogenesis among
222 chemicals tested in rodents by the U.S.NCI / NTP. Mutat
Res 204: 17-115.
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