1,2,4-trimethylbenzene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route

Dose descriptor:

NOAEC

2 500 mg/m³

Additional information

A three-generation reproduction/fertility study (McKee et al., 1990) using C9 aromatic naphtha (ASTM D-3734, Type 1) as the test substance, was conducted prior to current guidelines. Thirty rats/sex/dose level) were exposed via inhalation to 0, 100, 500, or 1500 ppm for 6 hours/day for 5 days/week for 10-12 weeks prior to mating and during the 2-week mating period.The males were exposed thereafter until termination but the F0 and selected F1 generation female rats were exposed until day 20 of gestation and then from postnatal day 5 until weaning at day 21. Exposure of the selected F1 and F2 offspring commenced approximately 1 week after all pups were weaned and from the day of weaning for selected F3 offspring.

 

The highest concentration of 1500 ppm was associated with the premature death of several females:3 F0 females died or were killed prior to mating, 3 during gestation and 1 during lactation; 3 F1 females died prior to mating, 1 during gestation, 1 during delivery and 1 on day 2 of lactation. Exposure of the F2 animals was continuous from postnatal day 5 and 88% died within the first week of exposure post-weaning, although a few did survive the duration of the study. The exposure concentration of 1500 ppm was considered to be in excess of the maximum tolerated dose for rats and therefore inappropriate for the evaluation of reproductive toxicity especially for the F2/F3 generations.

 

For the F0 generation,a dose-related reduction in body weight gain was observed in males and females exposed to 500 or 1500 ppm but reproductive parameters were unaffected. There were no differences in litter size, mean birth weight, or postnatal survival but the F1 offspring exposed to 1500 ppm group gained weight more slowly than controls.

 

For the selected F1 generation,a dose-related reduction in body weight gain was observed in males and females exposed to 500 or 1500 ppm; the effect at 1500 ppm was greater than seen previously in the F0 generation andclinical observations of ataxia and reduced motor activity were also observed indicating a more severe response to exposure. The fertility of the selected F1 males was reduced and the lack of detection of mating in approximately one third of the females resulted in exposure continuing until just prior to delivery. This extended exposure is considered by the authors to have caused reductions in the frequency of live births, mean birth weight and neonatal survival. However, evidence of reduced neonatal survival was also observed in litters whose mothers were exposed to 1500 ppm until day 20 of gestation.

 

For the selected F2 generation the severity of the toxicity due to 1500 ppm precludes meaningful evaluation of the reproductive data and, as a consequence, the significance of the observation of reduced male fertility and neonatal survival in the F1 generation exposed to this concentration cannot be put into context. Given the increased severity of the effect of 1500 ppm on the parental F1 generation compared to the F0 generation, the possibility of an effect of 1500 ppm on male fertility and neonatal survival cannot be dismissed.

 

On the basis of the results of this study, the NOAEC for reproductive toxicity is 500 ppm (equivalent to 2500 mg/m³according to Firth, 2008) although an effect of the higher concentration of 1500 ppm on reproduction has not been clearly established due to the overt toxicity seen. The NOAEC for systemic toxicity is 100 ppm (equivalent to 500 mg/m³according to Firth, 2008).  The test material contained a mixture of aromatics with similar molecular weight to trimethylbenzene and are assumed to have a similar toxicology profile therefore no adjustment is made to the NOAEC to account for the specific trimethylbenzene content.

Short description of key information:
In a 3-generation study using the inhalation route of exposure, a NOAEC of 2500 mg/m3 for reproductive toxicity was determined and a NOAEC of 500 mg/m3 for systemic toxicity.

Effects on developmental toxicity

Description of key information

Two inhalation prenatal developmental toxicity studies have been considered, one using rats and the other mice.  The most recent study conducted was reported.  It was well conducted to current guidelines and used the rat as the test species; a NOAEC of 1470 mg/m3 was determined for maternal and developmental toxicity.

Effect on developmental toxicity: via inhalation route

Dose descriptor:

NOAEC

1 470 mg/m³

Additional information

A well conducted developmental toxicity study to current guidelines has evaluated the exposure of rats to 1,2,4-trimethylbenzene by inhalation (Saillenfait et al., 2005). Female rats were exposed to 0, 100, 300, 600 or 900 ppm for 6 hours/day on days 6 – 20 inclusive, of gestation (where day 0 was the day of confirmation of mating and day 21 the day of termination). Reduced maternal body weight gain and food consumption were associated with exposure to 600 ppm and to 900 ppm; the NOAEC was 300 ppm. Foetal body weights were also reduced following maternal exposure to 600 or 900 ppm 1,2,4-trimethylbenzene but there was no evidence for an effect of treatment on foetal development and no evidence of teratogenicity. The reduction in foetal body weight was seen in the presence of an effect of 1,2,4-trimethylbenzene on maternal body weight gain. Thus, the NOAEC of 1,2,4 -trimethylbenzene for maternal and developmental toxicity in the rat was 300 ppm (1470 mg/m³).

 

An earlier developmental toxicity study (McKee et al., 1990) using C9 aromatic naphtha (ASTM D-3734, Type 1) as the test substance, was conducted prior to current guidelines. This study used mice as the experimental model and females were exposed to 0, 100, 500 or 1500 ppm for 6 hours/day on days 6 - 15 inclusive, of gestation (where day 0 was the day of confirmation of mating and day 18 the day of termination).

 

The exposure concentration of 1500 ppm was found to be in excess of the maximum tolerated dose for mice and 44% maternal lethality was caused; this concentration of 1,2,4-trimethylbenzene was therefore considered inappropriate for the evaluation of developmental toxicity in mice.

 

Maternal body weight gain was reduced during exposure to 500 ppm on gestation days 6 to 15 inclusive; foetal body weight was also reduced. However, there was no evidence for an effect of the test substance on foetal development and no evidence of teratogenicity. Thus, the NOAEC of C9 aromatic naphtha (ASTM D-3734, Type 1) for maternal and developmental toxicity in the mouse was 100 ppm (equivalent to 500 mg/m³ according to Firth, 2008).  The test material contained a mixture of aromatics with similar molecular weight to trimethylbenzene and are assumed to have a similar toxicology profile therefore no adjustment is made to the NOAEC to account for the specific trimethylbenzene content.

 

As1,2,4-trimethylbenzene is structurally similar to C9 aromatic naphtha (ASTM D-3734, Type 1) and is considered to have similar toxicity the results of these two studies can be used to confirm a highest NOAEC of 300 ppm /1470 mg/m³.

Justification for classification or non-classification

1,2,4-Trimethylbenzene is not toxic to reproduction and has no effect on fertility or development. Consequently, it does not warrant classification under DSD or CLP.