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International Journal of Toxicology 43(Supplement 1)
globules were observed. In the recovery group, a normal
lobular architecture and normal hepatocytes with rounded
vesicular nuclei were reported. The immunoperoxidase
technique was used to evaluate the Hep Par-1 immune reaction;
positive patchy immunoreactivity was observed in the
test group, and moderate immunoreaction in the cytoplasm of
most hepatocytes was observed in the recovery animals.
ParenteralTriethylhexyl Trimellitate
Six male albino rats were dosed intraperitoneally with 1.0 mg/
kg bw triethylhexyl trimellitate for 7 days, and the control
group was administered the same volume of saline.25 The
animals were killed 16 h after the last dose, and the livers were
removed. The test animals did not exhibit any signs oftoxicity,
and body weights and liver weights of the test animals were
similar to those of control animals. The effect of triethylhexyl
trimellitate on the activity of several enzymes was evaluated;
triethylhexyl trimellitate did not cause any change in the
activities of aminopyrine-N-demethylase, aryl hydrocarbon
hydroxylase, or glutathione-S-transferase, and it did not affect
glutathione levels.
Peroxisome Proliferation
Triethylhexyl Trimellitate. The induction of peroxisome proliferation
by triethylhexyl trimellitate has been studied because
triethylhexyl trimellitate has been considered as an
alternative to diethylhexyl phthalate (DEHP). In 21- and 28day
oral studies in Fischer 344 rats (described earlier), the
ability of triethylhexyl trimellitate (and DEHP and 2ethylhexanoic
acid) to induce peroxisomes was evaluated
using 3 enzyme markers, i.e., cyanide-insensitive palmitoyl
CoA oxidation, catalase, and carnitine acetyltransferase, and
the effect on numbers ofhepatic peroxisomes was evaluated.39
Peroxisome induction in rats given 2% triethylhexyl trimellitate
was less than that observed with .67% DEHP or in
those given a metabolically equivalent dose of 2ethylhexanoic
acid. The researcher also noted that a
" monoester effect " attributed to mono(2-ethylhexyl)phthalate
(MEHP) was not seen with triethylhexyl trimellitate.
A molecular modelling study of triethylhexyl trimellitate-
peroxisome proliferator-activated receptors (PPAR) interactions
was also conducted.45 Using a 3-dimensional model of
triethylhexyl trimellitate, in which flexible docking of the
compound into the receptor active site was performed using
GOLD 3.0.1 software, triethylhexyl trimellitate was not able
to fit in the binding site of either PPARα or PPARγ; the researchers
attributed this result to the size of the molecule.45
2-Ethylhexanoic acid appears to be a proximate peroxisome
proliferator in both mice and rats; however, even though
2-ethylhexanoic acid is a metabolite of triethylhexyl trimellitate,
triethylhexyl trimellitate appears only to have a
weak effect on peroxisome proliferation. Peroxisome proliferation
causes an increase in liver weights and can induce
hepatocarcinogenicity in rats and mice. However, peroxisome
proliferation is not believed to pose the risk of inducing
hepatocarcinogenesis in humans, as a species difference in
response to peroxisome proliferators exists, and in a previous
safety assessment the Panel noted that humans do not react to
peroxisome proliferators in the same manner that rodents do.4
There is no effect on organelle proliferation and induction of
peroxisomal and microsomal fatty acid-oxidizing enzymes in
species other than rats and mice, including humans. Consequently,
even iftriethylhexyl trimellitate were to have an effect
on peroxisome proliferation in rats or mice, these results
would have no relevance to humans.
Reproductive and Developmental Toxicity
In an oral developmental toxicity study, tricaprylyl/capryl
trimellitate had a NOAEL of 300 mg/kg bw/day for maternal
toxicity and of 1000 mg/kg bw/day for fetotoxicity in rats
dosed with up to 1000 mg/kg/day on days 6-15 of gestation29
(Table 7). In a reproductive and developmental toxicity study,
orally administered triethylhexyl trimellitate had a noobserved
effect level (NOEL) of 100 mg/kg/day in male
rats and 1000 mg/kg/day in female rats and offspring; spermatocytes
and spermatids were decreased with doses of 300
and 1000 mg/kg/day.32 Two oral developmental toxicity
studies with triethylhexyl trimellitate in rats (by gavage with
up to 1000 and 1050 mg/kg bw/day on days 14-18 and 6-19 of
gestation, respectively) did not produce any toxicologically
significant effects.32,46 Neither tricaprylyl/capryl trimellitate
nor triethylhexyl trimellitate, at doses of 500 mg/kg bw/day,
had a significant repressive effect on genes in the testicular
mal-development (TMD) pathway.29,32
In Vitro Tests for Endocrine Activity
Triethylhexyl Trimellitate. Triethylhexyl trimellitate was
screened in an in vitro competitive binding assay measuring its
binding affinity for the human estrogen receptor alpha
(ERα).47 Triethylhexyl trimellitate in dimethyl sulfoxide
(DMSO; 1010 to 104 mol/l) had no affinity for ERα in this
assay. It also did not have estrogenic activity in a yeast twohybrid
assay (an assay based on the ligand-dependent interaction
ofERα and the coactivator TIF2) at final concentrations
of103 to 107 mol/l in DMSO.48 The 10% relative effective
concentration (i.e., the concentration producing 10% of the
agonist activity of the highest activity level of 17 β-estradiol;
REC10) was >.001 mmol/l triethylhexyl trimellitate. The estrogenic
activity ofthe metabolites oftriethylhexyl trimellitate
(which were not identified) was also measured; the metabolite
solution was prepared by incubating triethylhexyl trimellitate
in S9 mix. The REC10 of the metabolite solution
was >.0005 mmol/l.
Triethylhexyl trimellitate in DMSO did exhibit estrogenic
activity in an in vitro test using human osteoblastic (US-O2)
reporter gene cell lines for ERα and ERβ.49 The lowest effective
concentrations of triethylhexyl trimellitate in the ERα

IJT - CIR - February 2024

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IJT - CIR - February 2024 - Cover3
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