IJT - CIR - February 2024 - 103S

Fiume et al.
103S
applications, with primary use in high-specification electrical
cable insulation and sheathing. It also has applications as a
plasticizer in medical products, specifically blood bags, infusion
sets, catheters, and hemodialysis tubing.24,25
Toxicokinetics
Absorption, Distribution, Metabolism, and Excretion
Tridecyl Trimellitate. Tridecyl trimellitate has a molecular
weight of 757 Da, low water solubility, and high log P value;
therefore, systemic availability from dermal exposure is expected
to be limited.9
Triethylhexyl Trimellitate. The in vitro hydrolysis of triethylhexyl
trimellitate (92% pure) was determined by adding
[hexyl 2-14C]triethylhexyl trimellitate (.19 µCi/mL) to rat
intestinal homogenates prepared from male Sprague-Dawley
rats.26 There was no evidence that triethylhexyl trimellitate
was hydrolyzed in the intestinal homogenates, and 2ethylhexanol
was not released.
The absorption, metabolism, and excretion of orally administered
triethylhexyl trimellitate (97.1% pure) was determined
in 4 fasted male Sprague-Dawley rats.2 The rats were
administered a single dose by gavage of100 mg/kg bw [hexyl2-14C]triethylhexyl
trimellitate (16-18 µCi) in corn oil, and
placed in metabolism cages. Urine, feces, and expired air were
collected at various intervals for up to 144 h, after which time
the animals were killed, several organs were removed, and the
radioactivity in these tissues was determined. The overall
recovery of radioactivity was 94.4% of the dose. Approximately
75% of the dose was excreted in the feces (actual
values ranged from 62.3-93.1% in the individual animals),
16% in the urine as metabolites (8.3-25.1% in the individual
animals), and 1.9% as expired 14CO2 (.8-3.5% in the individual
animals). Peak rates of excretion for expired 14CO2
were at 2-3 h and 8-12 h after dosing. Less than .6% of the
radioactivity remained in the tissues; the liver and adipose
tissues contained the greatest amounts. In the feces, 85% ofthe
radioactivity was excreted as unchanged triethylhexyl trimellitate,
and the remaining radioactivity as mono-(2-ethylhexyl)
trimellitate (1%), di-(2-ethylhexyl)trimellitate (7%),
and unidentified polar metabolites. In the urine, the metabolites
were identified as mono-(2-ethylhexyl)trimellitate, 2ethylhexanol,
2-ethylhexanoic acid, and 2-heptanone. Elimination
in the urine and in CO2 was biphasic, with half-lives of
3.1 and 42 h and 4.3 and 31 h, respectively. Figure 3 depicts
the metabolic fate of triethylhexyl trimellitate in rats.
The distribution and excretion of triethylhexyl trimellitate
was determined in male Sprague-Dawley rats.27 Serial blood
sampling was conducted with 5 rats dosed intravenously (i.v.)
with 10.5 mg/kg [14C-carbonyl]triethylhexyl trimellitate
(>98% radiochemically pure; 59.9 µCi/kg) in 2.5-3.5 mL ofa
soybean oil-water (10:90) emulsion. Blood samples were
collected prior to dosing, and at 10 time points from .5 to 336 h
(14 days) after dosing. The animals were placed in metabolism
cages, and urine and fecal samples were collected at various
intervals for 14 days. The distribution half-life, disposition
half-life, apparent distribution volume, and plasma clearance
were 46.2 min, 5.34 days, 7.49 L/kg, and 40.5 mL/kgh,
respectively, indicating 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;
renal clearance was 13 mL/kgh.
Twenty-eight rats were then dosed i.v. with 15.6 mg/kg
[14C-carbonyl]triethylhexyl trimellitate (28.0 µCi/kg) in 2.63.6
mL of the vehicle; groups of4 rats were killed at 1, 6, 24,
48, 72, 168, and 336 h after dosing. Blood samples, urine, and
feces were collected, and at necropsy, several organs were
removed and analyzed for radioactivity. The majority of the
radioactivity was distributed in the liver, lungs, and spleen.
The peak radioactivity in the liver was 71.6% of the dose at
24 h, in the lungs 18.6% at 1 h, and in the spleen 5.3% at 24 h;
the radioactivity in the liver and lungs declined after peaking,
and in the spleen, the amount of radioactivity recovered
mostly remained constant for 14 days.
Dermal Absorption
Triethylhexyl Trimellitate. Theinvitroskinabsorption of
triethylhexyl trimellitate was determined via analytical
methods in Franz cells using full-thickness skin samples
excised from female nude mice and specific pathogen-free
pigs.28 The receptor medium contained 40% ethanol, and the
donor medium was 5.4 mM triethylhexyl trimellitate in 40%
ethanol/pH 7.4 buffer. The skin samples were removed from
the cells after a 12 h exposure and tape-stripped. The accumulation
of triethylhexyl trimellitate was 1.32 ± .53 nmol/
mg in nude mouse and .35 ± .19 nmol/mg in pig skin; the flux
was 0 nmol/cm2/h for both mouse and pig skin. Triethylhexyl
trimellitate was not found in the receptor medium
after 12 h, indicating no biologically relevant availability for
dermal absorption.
Toxicological Studies
Single Dose (Acute) Toxicity
The acute dermal toxicity of tricaprylyl/capryl trimellitate (in
rats)29 and triethylhexyl trimellitate (in guinea pigs and rabbits)30,31
and the acute oral toxicity of tricaprylyl/capryl trimellitate
(in rats),29 tridecyl trimellitate (in rats),9 triethylhexyl
trimellitate (in mice and rats),32-35 and triisodecyl trimellitate
(in rats)36 was not remarkable (Table 5). 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,37 but no mortality was observed
with a 4-h exposure to 2600 mg/m3 in another study.38

IJT - CIR - February 2024

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IJT - CIR - February 2024 - Cover3
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