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EC number: 202-436-9
CAS number: 95-63-6
1,2,4- Trimethylbenzene has low systemic toxicity in rats when administered by inhalational or oral routes. No significant treatment-related effects were observed up to oral doses of 600 mg/kg/day or inhaled concentrations of up to 1800 mg/m3. Mild pulmonary lesions occurred, possibly as a result of respiratory irritation.
repeated dose studies have been conducted to evaluate both oral and
inhalation exposures to trimethylbenzenes. Typically
liver and kidney effects are reported at high doses together with some
acute central nervous system (CNS) effects. The focus in this evaluation
is on 1,2,4-trimethylbenzene where data is available, but read across
from other isomers is considered where specific data is unavailable. The
trimethylbenzene isomers have similar toxicological profiles (Firth
2008). There are no repeat dose toxicity data available in humans.
28-day study in rats was conducted on 1,2,4-trimethylbenzene (Biosafety
Research Center,1996). Administered
doses were 0, 30, 100, 300 and 1000 mg/kg/day with primary effects
reported at the top two doses including increased liver and kidney
weights and increased salivation. Weight
gain was suppressed at the highest dose level. No
haematological changes or abnormalities at necropsy were reported. The
NOAEL was 100 mg/kg/day.
90-day oral study is not available for 1,2,4-trimethylbenzene, but a
study is available on the isomer 1,3,5- trimethylbenzene. In
this oral gavage study, rats were dosed at 0, 50, 200, and 600
mg/kg/day, with a recovery group being dosed at 600 mg/kg/day and
observed for 28 days post-treatment. In the 600 mg/kg/day group an
increase in serum phosphorus levels (males and females), liver weight
increases (absolute and relative weight increase in females; relative
increase only in males) and kidney weight increases in males were
the recovery group, no apparent effects were reported at the end of the
28-day recovery period.
on the recovery group data, the effects reported at the highest dose
were considered reversible and were attributed to an adaptive response
(enzyme induction) to the test substance. Liver growth is likely to be
due to microsomal enzyme induction whilst the increased kidney weights
in male rats are likely to be due to alpha-2µ-globulin related
respect to the elevated serum phosphorus levels observed, these levels
were not statistically different at the end of the 28-day recovery
period and no associated histopathological effects were reported which
could be correlated with the increased serum phosphorus levels. The
NOAEL for this study was therefore concluded to be 600 mg/kg/day.
are no repeat dose dermal studies available but testing
via the dermal route is not required as human skin contact is unlikely
and in accordance with column 2 of REACH Annex VIII, testing shall be
performed using the most appropriate route of administration.
The key study is
considered to be a 12 month chronic inhalation toxicity study with high
flash aromatic naptha (a 50:50 blend of Shellsol A and Solvesso 100,
which contains 44.81% total trimethylbenzene, all isomers) in rats
(Clark et al, 1989). Rats were exposed to the aromatic solvent blend at
concentrations of 0, 450, 900 or 1800 mg/m3 6 h/day, 5 days/week for 52
weeks. An initial reduction in body weight gain occurred in both male
and female rats at the higher exposures. Various statistically
significant haematological changes were transiently seen in males up to
six months, but were not considered biologically significant. High
exposure male liver and kidney weights were increased at 6 and 12 months
but, in the absence of histopathological changes, were considered to be
physiological adaptive responses. Some rats in all exposure groups and
the control group showed mild pulmonary macrophage infiltration and
alveolar wall thickening however there was no appreciable difference between
the groups and no evidence that
exposure had influenced the incidence or severity of the changes.
Overall, no treatment-related histopathological abnormalities were
found. It was concluded that chronic exposure to this high aromatic
naphtha was without systemic toxicity in rats under the conditions of
this study with a NOAEC of 1800 mg/m3. The
test material contained a mixture of di- and tri-alkyl benzenes
(including methyl-ethylbenzene isomers and other trimethylbenzene
isomers) possessing presumably similar physico-chemical and
toxicological properties therefore no adjustment was made to the NOAEC
to account for the specific trimethylbenzene content.
These data are
supported by the studies of Korsak et al (1997, 2000 a & b). In these
studies, rats were exposed to nominal vapour concentrations of 0, 123,
492 or 1230 mg/m3 of 1,2,4- trimethylbenzene or 1,3,5- trimethylbenzene
for 90 days (6h/day, 5 days/week). In all 3 studies, all animals
survived and there were no effects on body weight and no clinical signs
of toxicity. The
90 day studies (Korsak 2000 a & b), resulted in an overall low degree of
systemic toxicity. Adaptive effects of exposure to 1,2,4-
trimethylbenzene and 1,2,3 - trimethylbenzene included slightly
increased sorbitol dehydrogenase activity and some blood changes
(decreased red and increased white blood cell counts), observed at 1230
lesions, comprising an increase in peribronchial, lung parenchymal and
perivascular lymphocytic infiltration, were described by the authors at
492 and 1230 mg/m3 for both isomers, however the pathology was poorly
reported. Since no comparable findings were reported by Clark et al.
(1989) in a study of longer duration it is concluded that these findings
are of limited relevance to hazard identification. There were no
significant histopathological changes in the upper respiratory tract or
in any other organs examined, demonstrating the lack of systemic
effects. The overall systemic NOAEC from these investigations by Korsak
et al. is therefore considered to be 1230 mg/m3 for both isomers.
In the supporting
respiratory irritation study (Korsak et al, 1997), bronchiolar lavage
was collected at termination (24 h after the last exposure) and BAL
were stained and examined by light microscopy. Differential cell counts
were made and cell viability was assessed using the trypan blue test.
There was an increased number of cell macrophages, polymorphonuclear
leukocytes and lymphocytes at all three test concentrations compared
with the controls. Total protein lactate dehydrogenasee (LDH) and acid
phosphatase activity in BAL
significantly increased in all exposed groups. However, the observed
changes were not concentration-dependent, showing no progression of
effects even with an exposure 10 times higherTherefore, although
respiratory irritation effects were observed in the BAL
even at the
lowest concentration of 123 mg/m3, there were no toxicologically
significant clinical effects at concentrations up to and including 1230
Trimethylbenzene has low systemic toxicity in rats when administered by
inhalational or oral routes. An oral NOAEL of 600 mg/kg day was
established from a 90 day study on 1,3,5-trimethylbenzene and an
inhalational NOAEC of 1800 mg/m3 has been established from a 12 month
study on high flash aromatic naphtha.
(1994) Scientific Expert Group on Occupational Exposure Limits for
1,2,4-Trimethylbenzene has low oral and
inhalational sub-chronic toxicity and dermal exposure is unlikely. It
does not therefore warrant classification under DSD or CLP.
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