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EC number: 202-436-9
CAS number: 95-63-6
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
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
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.
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
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.
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.
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.
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).
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).
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.
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.
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.
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