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International Journal of Toxicology 43(Supplement 1)
study was 225 mg/kg bw/day; some effects were observed in
liver and spleen weights.
Oral administration of 300 mg/kg/day triethylhexyl trimellitate,
6 days/wk for 4 wk, produced mild reversible effects
in the liver of rats; evaluation of the Hep Par-1immune reaction
reported positive patchy immunoreactivity in the test
group, and moderate immunoreaction in the cytoplasm of
most hepatocytes was observed in recovery animals. Intraperitoneal
administration of 1.0 mg/kg bw triethylhexyl trimellitate
for 7 days did not have an effect on hepatic enzymes.
Orally administered triethylhexyl trimellitate (21- or 28days)
did not have a remarkable effect on peroxisome proliferation
in rats.
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 ofgestation. In
a reproductive and developmental toxicity study, orally administered
triethylhexyl trimellitate had a NOEL for reproductive
and developmental effects 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. 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. Neither tricaprylyl/capryl trimellitate nor
triethylhexyl trimellitate, at doses of500 mg/kg bw/day, had a
significant repressive effect on genes in the TMD pathway.
Several studies were performed to evaluate whether triethylhexyl
trimellitate had endocrine disrupting activity.
Triethylhexyl trimellitate (1010 to 104 mol/l, in DMSO) had
no affinity for ERα in a competitive binding assay, and it did
not have estrogenic activity in a yeast two-hybrid assay (101
to 105 mol/l, in DMSO). However, in a study evaluating
estrogenic potency using ERα and ERβ reporter gene cell
lines, triethylhexyl trimellitate in DMSO was shown to be
estrogenic in both cell lines.
Tricaprylyl/capryl trimellitate and triethylhexyl trimellitate
were not genotoxic in the Ames test using Salmonella typhimurium,
a mammalian cell gene mutation assay in mouse lymphoma
cells, or a chromosomal aberration assay in human lymphocytes or
Chinese hamster lung fibroblasts (for triethylhexyl trimellitate),
and triethylhexyl trimellitate was not genotoxic in a forward
mutation assay in Chinese hamster ovary cells, unscheduled DNA
synthesis assay in rat primary hepatocytes, or dominant lethal
assay in mice. Also, urine from rats dosed with triethylhexyl
trimellitate was not mutagenic in the Ames test.
Undiluted tricaprylyl/capryl trimellitate, 10% tridecyl trimellitate,
and triisodecyl trimellitate were slightly irritating to
rabbit skin following a single occlusive application, but undiluted
tridecyl trimellitate was non-irritating to mouse skin. A
single occlusive application of undiluted triethylhexyl trimellitate
produced reversible moderate erythema and moderate
to severe edema in guinea pig skin; triethylhexyl
trimellitate was a reversible primary dermal irritant in Californian
rabbits, but it was not a primary irritant in New
Zealand White rabbits. In clinical testing, a lipstick formulation
containing 22.3% tridecyl trimellitate was not irritating,
and did not induce a phototoxic response.
Tricaprylyl/capryl trimellitate (10% at induction/undiluted
at challenge) was not a sensitizer in a guinea pig maximization
study, and undiluted triethylhexyl trimellitate was not a
sensitizer in a Buehler sensitization assay in guinea pigs. Up to
100% tridecyl trimellitate was negative in a local lymph node
assay. In human repeated insult patch tests, tridecyl trimellitate
(57.1% in a lipstick formulation and undiluted) and 1%
triethylhexyl trimellitate were not sensitizers.
Tricaprylyl/capryl trimellitate, triethylhexyl trimellitate,
and triisodecyl trimellitate were not irritating to rabbit eyes,
and tridecyl trimellitate was slightly irritating to rabbit eyes.
Discussion
The trialkyl trimellitates form a family ofcosmetic ingredients
in that they are all structurally related as alkyl esters of the
aromatic triprotic acid, trimellitic acid. The only structural
difference between the ingredients included in this family is
the length/branching of the alkyl chains.
The Panel discussed the fact that triethylhexyl trimellitate
exhibited estrogenic activity in an in vitro test using human
osteoblastic (US-O2) reporter gene cell lines for ERα and
ERβ. However, trialkyl trimellitates are not significantly absorbed
through the skin, thus the Panel was not concerned with
potential endocrine effects.
It was noted that some studies suggested the induction of
peroxisome proliferation by triethylhexyl trimellitate in rats.
However, triethylhexyl trimellitate appeared only to have a
weak effect on peroxisome proliferation. The Panel further
noted that even ifthere was an effect, peroxisome proliferation
is not believed to pose the risk of inducing hepatocarcinogenesis
in humans because humans do not react to peroxisome
proliferators in the same manner as rodents.
The Panel noted that no carcinogenicity data were available.
They concluded that carcinogenicity is not a concern
with cosmetic use because tricaprylyl/capryl trimellitate and
triethylhexyl trimellitate are not genotoxic, there is a lack of
structural alerts for carcinogenicity, and the dermal absorption
is expected to be poor.
There was concern that the potential exists for dermal irritation
with the use of products formulated using trialkyl trimellitates.
Therefore, the Panel specified that products containing
these ingredients must be formulated to be non-irritating.
Finally, the Panel recognized that there were little toxicity
data available for the branched ingredient triisodecyl trimellitate.
However, an analogous ingredient, triethylhexyl
trimellitate, was found to have no biologically relevant
availability for dermal absorption in mouse or pig skin
samples. Therefore, the Panel had little concern about the
safety of triisodecyl trimellitate as used in cosmetics.

IJT - CIR - February 2024

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Contents
IJT - CIR - February 2024 - Cover1
IJT - CIR - February 2024 - Cover2
IJT - CIR - February 2024 - 1S
IJT - CIR - February 2024 - 2S
IJT - CIR - February 2024 - Contents
IJT - CIR - February 2024 - 4S
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IJT - CIR - February 2024 - Cover3
IJT - CIR - February 2024 - Cover4
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