IJT - CIR - February 2024 - 115S

Fiume et al.
115S
Table 10. Ocular Irritation Studies.
Test Article
Concentration/
Dose
tricaprylyl/
capryl
trimellitate
tridecyl
trimellitate
not specified
(assumed to be
undiluted)
triethylhexyl
trimellitate
as supplied; .1 mL small
Animals
Method
NON-HUMAN STUDIES
the test
White Russian
rabbits, 3
material was instilled into the
conjunctival sac of 1 eye; the
eyes were rinsed after 72 h
NZW rabbits, 3 study conducted using methods
similar to those of the OECD
TG 405 (i.e., acute eye
irritation/corrosion test;
additional details were not
provided)
as supplied; .1 mL 6 NZW rabbits (sex
not specified)
triisodecyl
trimellitate
as supplied; .1 mL NZW rabbits, 3M/
3F
the test material was instilled into
the conjunctival sac of the right
eye; the eyes were not rinsed
the test material was instilled into
the conjunctival sac of 1 eye;
the eyes of 3 animals were
rinsed after 30 sec
Results
non-irritating
No signs of irritation at 24, 48,
or 72 h
slightly irritating
Severe conjunctival effects
observed at 1 h; effects
diminished in severity by 24
h, and were resolved by 72 h
not a primary ocular irritant;
average ocular irritation
score was 2.3/110 on day 1,
1.7/110 on day 2, and 0 on
days 3-7
not irritating
Very slight conjunctival
reactions were observed in 2
rinsed and 3 unrinsed eyes at
1 h; all rinsed eyes and 1
unrinsed eye were normal at
24 h; all eyes were normal at
48 h
Abbreviations: NZW, New Zealand White; OECD, Organisation for Economic Development; TG, test guideline.
are used in cosmetic formulations; tricaprylyl/capryl trimellitate
is the only ingredient in this group that is not reported
to be used. Tridecyl trimellitate has the greatest frequency and
concentration of use; it is reported to be used in 409 formulations,
and the maximum reported concentration of use is
57.1% in lipstick formulations.
Tridecyl trimellitate has a molecular weight of757 Da, low
water solubility, and high log P value; therefore, systemic
availability is expected to be limited under conditions of
cosmetic use. In rats, approximately 75% ofa single oral dose
of 100 mg/kg bw [hexyl-2-14C]triethylhexyl trimellitate was
excreted in the feces, 16% in the urine as metabolites, and
1.9% as expired 14CO2. In the feces, 85% of the radioactivity
was excreted as unchanged triethylhexyl trimellitate, and the
remainder as mono-(2-ethylhexyl) trimellitate (1%), di-(2ethylhexyl)trimellitate
(7%), and unidentified polar metabolites.
The urinary metabolites were identified as mono-(2ethylhexyl)trimellitate,
2-ethylhexanol, 2-ethylhexanoic acid,
and 2-heptanone. In rats dosed i.v. with [14C-carbonyl]
triethylhexyl trimellitate, there was a fairly rapid initial distribution
and slow clearance of triethylhexyl trimellitate from
the body; over the 14-day period, 3.3% of the radioactivity
was recovered in the urine and 16.9% was recovered in the
feces. In a 28-day i.v. study examining the distribution of
triethylhexyl trimellitate in rats, the majority of the radioactivity
was distributed in the liver, lungs, and spleen.
In in vitro dermal absorption studies with skin from nude
mice and specific pathogen-free pigs, the accumulation of
triethylhexyl trimellitate in the skin was 1.32 ± .53 nmol/mg
and .35 ± .19 nmol/mg, respectively. Triethylhexyl trimellitate
was not found in the receptor medium after 12 h, indicating no
systemic availability for dermal absorption.
The acute dermal toxicity of tricaprylyl/capryl trimellitate
and triethylhexyl trimellitate, and the acute oral toxicity of
tricaprylyl/capryl trimellitate, tridecyl trimellitate, triethylhexyl
trimellitate, and triisodecyl trimellitate, were not remarkable.
Mixed results were observed with triethylhexyl trimellitate in
single-exposure inhalation studies in rats; 100% mortality was
reported with a 6-h whole body exposure to heated vapor with
2640 and 4170 mg/m3 in one study, but no mortality was
observed with a 4-h exposure to 2600 mg/m3 in another study.
In repeated dose oral toxicity studies in rats, the NOAEL of
tricaprylyl/capryl trimellitate was 300 mg/kg/day in a 28-day
gavage study (a slight but statistically significant increase in
absolute and relative liver weights was observed in males and
females dosed with 1000 mg/kg/day), and was 500 mg/kg/day
in a 13-wk gavage study. Triethylhexyl trimellitate was administered
to rats by gavage for 21-days (up to 2000 mg/kg/
day)39,40 or 28-days (up to 1000 mg/kg/day), and in the diet
(up to 2%) for 28 days and (up to 1000 mg/kg/bw) for 90 days.
In the feed study, hepatomegaly was reported with .67 and
2.0% triethylhexyl trimellitate. The NOAEL in the 90-day
63
9
Reference
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