Registration Dossier

Administrative data

Description of key information

1,2,4- Trimethylbenzene is irritating to the skin and eyes of rabbits. Respiratory irritation (decreased respiratory rate) was observed in mice with 2842 mg/m3 producing a 50% decrease. No respiratory irritation was noted in human studies but these were conducted at much lower doses than the animal studies.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Non-human information

Skin

There is no data on 1,2,4-trimethylbenzene itself but the trimethylbenzene isomers have similar toxicological profiles (Firth 2008). The key study is provided by Jacobs and Martens (1987) where the skin irritation potential of the isomer, 1,3,5-trimethylbenzene (mesitylene), was investigated on shaved rabbit skin. A sample (0.5 mL) was applied under occlusion for 4 hr with an area of untreated skin serving as control. The overall mean score for erythema (for all animals over a 72 hour period) was 2.33; no oedema was reported. The results indicate that 1,3,5-trimethylbenzene is irritating to rabbit skin. This study is supported by other data on 1,3,5-trimethylbenzene demonstrating that concentrations in excess of 25% were irritating to rabbit skin (Jacobs et al, 1987). A study on undiluted Shellsol A (a mixture of trimethylbenzenes CAS# 64742-95-6) also showed that this was a moderate skin irritant following a single 24 hour application to abraded and non-abraded occluded rabbit skin.

In conclusion, the data indicate that 1,2,4-trimethylbenzene has the potential to be irritating to skin.

 

Eye

1,2,4 -Trimethylbenzene is irritating to the eye. This was concluded by SCOEL (1994) in relation to all the trimethylbenzene isomers, but the only reference available is an IUCLID 4 entry (ESBI, 1990) where the results of a rabbit occular irritation test showed that 1,2,4- trimethylbenzene was irritating to the eyes, but details are lacking and the study cannot be sourced. An earlier study on Shellsol A (a mixture of trimethylbenzenes# 64742-95-6) showed that one drop instilled into the rabbit eye caused an immediate pain reaction but thereafter was practically non-irritating.

In spite of these apparently conflicting results, and in the absence of reliable information to the contrary, the harmonized EU position (indicating the 1,2,4- trimethylbenzene is irritating to the eye) is retained.

 

Respiratory tract

 

Respiratory sensory irritation effects of 1,2,4-trimethylbenzenes in male Balb/C mice were investigated under conditions of acute exposure (Korsak et al, 1997). Male Balb/C mice were exposed to trimethylbenzenes for 6 min. Respiratory sensory irritation was quantified by determination of the decrease in respiratory rate. 1,2,4-trimethylbenzene depressed respiration rate and the concentration at which the respiratory rate was decreased to 50% (RD50) was 578 ppm (2842 mg/m3). A 90 day study is also described in the same publication (see Section on Repeat dose Toxicity). Rats were exposed to 1,2,4-trimethylbenzene for 90 days, at concentrations of 25, 100 and 250 ppm. There was no evidence of systemic toxicity at concentrations up to and including 250 ppm (1230 mg/m3). The total number of cell macrophages, polymorphonuclear leukocytes and lymphocytes in the brochiolar lavage (BAL) fluid at all three test concentrations was increased compared with the controls. Total protein lactate dehydrogenase and acid phosphatase activity in BAL were also increased in all exposed groups. These changes are indicative of mild respiratory irritation, however, a concentration-dependency was not seen, and therefore some adaptation may have taken place.

In conclusion, these data indicate that 1,2,4-trimethylbenzene has the potential to be irritating to the respiratory tract.

 

 

Human Information

 

Some information is available on the potential for trimethylbenzenes to cause irritation in humans. In human volunteer toxicokinetics studies on inhaled trimethylbenzenes, subjects were asked to assess (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 at concentrations up to 120 mg/m3 (Jarnberg et al, 1996).

 

Conclusions

The available data from animal studies indicates that 1,2,4-trimethylbenzene, in common with other trimethylbenzene isomers, is irritating to skin, eyes and respiratory tract. Although no adverse effects were noted in human volunteer studies these were conducted at concentrations at least an order of magnitude lower than those in animal studies. Reference Firth MJ (2008). Derivation of a chronic reference dose and reference concentration for trimethylbenzenes and C9 aromatic hydrocarbon solvents. Reg Tox. Phamacol. 52, 248-256

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

1,2,4 -Trimethylbenzene is classified as irritating to skin, eyes and respiratory tract: Xi, R36, R37 and R38 under DSD; this is equivalent to a classification of Category 2, H319 Causes serious eye irritation, H335 May cause respiratory irritation and H315 Causes skin irritation, under CLP.