1,2,4-trimethylbenzene

Endpoint summary

Description of key information

The acute oral and dermal LD50 values for 1,2,4-trimethylbenzene are concluded to be  greater than 3000 mg/kg. In acute inhalation studies the LC50 is reported as 18,000 mg/m3. In human volunteer studies no effects were reported at concentrations up to 150 mg/m3.

Key value for chemical safety assessment

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

18 000 mg/m³

Additional information

Non-human information

Oral

In a key study (MB Research Laboratories Inc, 1980) rats were given single oral doses of from 3000-10,000 mg/kg body weight of 1,2,4 –trimethylbenzene (pseudocumene). Lethargy and ptosis were seen at all four dose levels while ataxia and piloerection were only seen at the three highest levels. The LD50 in this study was 6000 mg/kg. This result is supported by the studies of Litton Bionetics Inc (1976) where the LD50s for male and female rats were 3550 and 3280 mg/kg respectively and Lewis (2003) where oral LD50 values of greater than 5000 mg/kg have been reported in rats. The oral toxicity of 1,2,4 –trimethylbenzene is similar to that the other trimethylbenzene isomers in comparative studies on the isomers (Lewis, 2003) and studies on isomer mixtures (Shellsol A -a mixture of trimethylbenzenes CAS# 64742-95-6) where an acute oral LD50 of greater than 8 mL/kg bw ( 6880 mg/kg) and approximately 4 mL/kg bw (3440 mg/kg) were reported for male and female rats respectively (Shell Toxicology Laboratory, 1977).

In conclusion, the oral LD50 of 1,2,4-trimethylbenzene in rats is greater than 3000 mg/kg

 

Inhalation

Information from robust studies on the inhalational acute toxicity of 1,2,4 –trimethylbenzene is lacking. An LC50 value of 18,000 mg/m3 in rats has been reported for 1,2,4-TMB (Lewis, 2003), although details of the original studies are lacking. Further details are given in the review of Firth et al (2008). As this is not a primary reference (Klimisch 4) it has not been designated as a key study although the LC50 below 20,000 mg/m3 leads to classification under DSD and CLP as harmful by inhalation.

An adequate, key study is provided by Shell Toxicology Laboratory (1977). Rats were exposed for 4 hours to Shellsol A (a mixture of trimethylbenzenes CAS# 64742-95-6) at 10,200 mg/m3. There were no deaths and no adverse signs other than lethargic behaviour. The acute LC50 was greater than 10,200 mg/m3. This result is supported by Cameron et al (1938) where a 12 hour LD50 was greater than 9833 mg/m3 in rats and mice. Korsak and Rydzynski (1996) tested rotarod performance and pain sensitivity behaviour in rats exposed to 1,2,4 –trimethylbenzene for 4 hours. Disturbances in rotarod performance and decreased pain sensitivity occurred with EC50 values for rotarod performance being 4690 mg/m3 and for pain sensitivity being 5679 mg/m3. Korsak et al (1997) investigated the effect of 1,2,4 –trimethylbenzene on respiratory sensory irritation in male mice after acute exposure to 2842 mg/m3 but this study is described in the “Irritation Section”. The inhalational toxicity of 1,2,4 –trimethylbenzene is also similar to that the other trimethylbenzene isomers in comparative studies on the isomers (Lewis, 2003, Korsak et al 1997)

In conclusion, the available data indicates that 1,2,4-trimethylbenzene has low acute inhalational toxicity at exposures up to approximately 10,200 mg/m3. However, the secondary reference of Lewis indicates an LC50 in rats below 20,000 mg/m3.

 

Dermal

Some information is available for the acute toxicity of 1,2,4- trimethylbenzene by dermal application. One dermal acute study showed an LD50 value of greater than 3440 mg/kg after exposure of rats to Shellsol A (a mixture of trimethylbenzenes CAS# 64742-95-6) for 24 hours (Shell Toxicology Laboratory, 1977). A poorly reported study (IUCLID 4 record) in guinea pigs indicated that there were no deaths when guinea pigs were exposed to 1,2,4 -trimethylbenzene (Solvesso 100) at approximately 890 and 1695 mg/kg by dermal application (ESBI 1975)

 

 

Human information

There is no information available on the effects of trimethylbenzenes in humans after oral and dermal exposure. Information on the effects of inhaled 1,2,4-trimethylbenzene is available from human volunteer toxicokinetics studies and indicates no signs of toxicity for exposures up to 150 mg/m3. Jarnberg et al (1996) assessed the toxicokinetics of inhaled trimethylbenzenes in man. Ten male volunteers were exposed to 120 mg/m3 of 1,2,4-TMB for 2 hours in an exposure chamber at a constant work load of 50 W on an ergometer bicycle. Before, during and after exposure the subjects rated symptoms related to irritation or the central nervous system from "no effect at all" to "almost unbearable" for (i) Discomfort in eyes: burning, irritation, or running eyes; (ii) discomfort in nose: burning, irritation, or running nose; (iii) discomfort in throat or airways; (iv) headache; (v) fatigue; (vi) nausea; (vii) dizziness; (viii) intoxication; (ix) difficulty in breathing and (x) smell of solvent. No effects were reported. Kostrzewski et al (1997) also exposed human volunteers to up to 150 mg/m3 for 4 or 8 hours. Clinical examinations (internal, laryngologic, neurologic and haematologic) were carried out before the onset of exposure, after exposure and repeatedly after the experiment at 3 month intervals but no abnormalities were detected.

 

 

Conclusions

Exposure via the oral and inhalational routes are the most relevant for 1,2,4-trimethylbenzene. Data in rats indicate a low potential for acute oral toxicity with the oral LD50 of 1,2,4-trimethylbenzene in rats being greater than 3000 mg/kg. Inhalational exposure of humans up to 150 mg/m3 resulted in no acute toxicity but the LC50 in rats of 18,000 mg/m3 results in its being classified as harmful by inhalation.

Justification for classification or non-classification

No classification for acute oral or dermal toxicity is warranted under DSD or CLP. 1,2,4 -Trimethylbenzene is classified as harmful by inhalation under DSD (Xn, R20) and this is equivalent to a classification of Acute Tox Category 4, H332: Harmful if inhaled, under CLP.

The kinematic viscosity of 1,2,4 -trimethylbenzene justifies classification Xn, R65, under DSD and, under CLP, Aspiration Tox Category 1, H304