1,2,4-trimethylbenzene

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
Dermal absorption of 1,2,4-TMB is low at 0.057%

Additional information

Non-human information

Absorption

When male rats were exposed by inhalation to 25, 100 or 250 ppm 1,2,4-trimethylbenzene for 6 hours, concentrations of 1,2,4-trimethylbenzene in blood increased rapidly reaching a plateau before the end of the exposure period. Absorption half lives increased with dose from 38 minutes at 25ppm to 101 minutes at 250ppm (Swiercz et al., 2002).

Distribution

After repeated exposures (6 hour/day, 5 day/week for 4 weeks), concentrations of 1,2,4-trimethylbenzene in liver, lung and brain were similar and increased with atmospheric concentration of 1,2,4-trimethylbenzene. Concentrations of 1,2,4-trimethylbenzene in liver were significantly lower following repeated exposures than after a single exposure; this may indicate induction of metabolising enzymes (Swiercz et al., 2003).

Metabolism

Following exposure by inhalation to 1,2,4-trimethylbenzene, 3,4-, 2,4-, and 2,5-dimethylbenzoic acids (3,4-DMBA, 2,4-DMBA and 2,5-DMBA) were all present in blood; concentrations of 3,4-DMBA were greatest. There was an approximately linear relationship between the concentration of each metabolite in blood and the atmospheric concentration of 1,2,4-trimethylbenzene. The relative amounts of each DMBA isomer present in blood is dependent on the metabolic rate constants; those for 3,4-DMBA (V_max 96mg/h/kg; K_m 28mg/L) being greater than for the other isomers (V_max 25mg/h/kg; K_m 7mg/L) (Swiercz et al., 2003). Repeated inhalation exposure to high vapour concentrations of 1,2,4-trimethylbenzene (5,000 mg/m3, 8 hr/d for 3 days) appeared to result in increased metabolism (and clearance) of 1,2,4-trimethylbenzene from blood and brain (McKee et al., 2010).

Excretion

Blood concentrations of 1,2,4-trimethylbenzene showed a biphasic decline following exposure by inhalation to 1,2,4-trimethylbenzene for 6 hours. Terminal half lives increased with dose from 217 minutes at 25ppm to 1140 minutes at 250ppm (Swiercz et al., 2002).  After repeated exposures (6 hour/day, 5 day/week for 4 weeks), terminal elimination half lives again increased with atmospheric concentration of 1,2,4-trimethylbenzene from 173 minutes at 25 ppm to 594 minutes at 250ppm but were shorter than after a single exposure indicating possible induction of metabolising enzymes (Swiercz et al., 2003).

Human information

When human volunteers were exposed to 2 or 25 ppm 1,2,4-trimethylbenzene by inhalation for 2 hours, the respiratory uptake was approximately 64% and was independent of atmospheric concentration of 1,2,4-trimethylbenzene. Concentration of 1,2,4-trimethylbenzene in arterial blood increased rapidly without reaching any plateau within the exposure period. Approximately 20% of the respiratory uptake of 1,2,4-TMB was exhaled unchanged during and after exposure while less than 0.002% was excreted unchanged in urine within 4 hours post-exposure. The kinetics of 1,2,4-trimethylbenzene were characterised by a large volume of distribution and long terminal elimination half life (Jarnberg et al., 1996). 

Following a 4 hour exposure by inhalation (5-150 mg/m³), the retention of 1,2,4-trimethylbenzene in the lungs was 68%. Elimination of 1,2,4-trimethylbenzene from capillary blood following exposure at 150 mg/m³showed a triphasic decline with a terminal life of approximately 44 hours. The elimination of DMBA isomers from urine following exposure at 150 mg/m³ was biphasic with a terminal half life of approximately 63 hours for all isomers (Kostrzewski et al., 1997).

Linear relationships were found between the air concentrations of the read-across substance 1,3,5-trimethylbenzene and the concentration of unchanged 1,3,5-trimethylbenzene and its metabolite 3,5-dimethylbenzoic acid as well as the unchanged substance in blood (Janasik et al., 2008).

Comparative metabolism and uptake of trimethylbenzene isomers

Both Jarnberg et al. (1996) and Kostrzewski et al. (1997) studied the toxicokinetics of the three isomers of trimethylbenzene in human volunteers. Respiratory uptake was similar; 64±3, 56±4 and 62±3% for 1.2,4, 1,2,3 and 1,3,5-trimethylbenzene respectively. The percentage of the respiratory uptake exhaled unchanged was similar for 1,2,4 and 1,3,5-trimethylbenzene (20±3 and 25±6% respectively) but was higher for 1,2,3-trimethylbenzene (37±9%); in all cases the amount excreted unchanged in urine was negligible. The three isomers were all metabolised to isomers of dimethylbenzoic acid; the number of isomers formed depending on the number of unique substitution patterns available.

Discussion on absorption rate:

The in-vitro percutaneous absorption of 1,2,4 -trimethylbenzene has been determined after applying a dose of 128 µL 1,2,4 -trimethylbenzene to occluded skin from a human donor (exposed area = 0.64 cm²).  Steady state conditions were not attained within 8 hours; the amount absorbed was 64 µg, equivalent to 0.057% of the applied dose (Korinth et al., 2003).