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EC number: 203-812-5
CAS number: 110-88-3
When 40 and 400 mg/kg were applied intraperitoneally to rats, [14C]-trioxane
was rapidly absorbed from the intraperitoneal cavity, metabolized and
excreted (Ligocka et al., 1998). Due to this high turnover no
accumulation should be expected.
The main excretion pathway is the exhaled air (87%, 24h following
administration) and urine (2.2%, 24h following administration).
The maximum excretion rate was observed 2h following i.p. injections.
With low concentrations (40 mg/kg bw) the main exhaled metabolite was
carbon dioxide and the elimination of radioactivity was monophasic. The
total elimination rate was determined to be 81-90% within 72h after
administration and the half-life was calculated as 3.5 h.
With increasing, saturating dosages a significant amount (8% at 400
mg/kg bw) of unchanged trioxane was found in exhaled air.
With low concentrations (40 mg/kg bw) almost all of the radioactivity in
the blood was bound to plasma components, whereas with rising,
saturating dosages a significant amount of radioactivity is bound to the
erythrocytes (10x higher binding efficiency than to plasma at 400 mg/kg
The elimination from blood plasma was biphasic and it was postulated
that this is reflecting the different excretion constants for unchanged
trioxane and CO2 (t ½ 4.5 and 72 h).
The tissue distribution of 14C is comparatively low (approx.
1.2% in total) and the decline is rapid. Highest concentrations were
found in liver, plasma and kidney 2h following i.p. application, lowest
concentrations were found in fat tissue, sciatic nerve and brain.
Similar tissue distributions were found following a single oral gavage
of [14C]-trioxane to pregnant rats (Sitarek et al., 1990). In
maternal animals, 3 h after dose administration, the highest levels of
total radioactivity were detected in the liver and plasma, followed by a
slow gradual decline with time.
The radioactivity content in whole fetus was comparable to that of the
maternal kidney. Unlike in the maternal animals, total radioactivity in
liver and kidney of fetuses was higher 48h compared to 3h following
application of trioxane. After 48h total radioactivity in fetal kidney
and brain was more than twice as high as in the corresponding maternal
organs. Hence trioxane and/or its metabolites are transported to the
fetus via the placenta.
Since no total recovery of the applied radioactivity was reported, no
conclusion on the oral absorption rate can be made.
Oral absorption was shown to be readily and almost complete in an
incompletely reported gavage study in rats
(Biodynamics, 1980). 72 h following single application of 2500 mg/kg bw [14C]-trioxane,
72% of the radioactivity were recovered in the exhaled air, 15% in
urine, 2% in internal organs and tissues and only less than 1% in feces.
Unfortunately no toxicokinetic studies following the
inhalation and the dermal routes of exposure are available. In absence
of toxicokinetic data the ECHA Guidance Chapter R.7C is explicitly
encouraging considerations on the possible activity profile of a
substance derived from physico-chemical and other data, as well as
structurally related substances with respect for argumentation on
waiving or triggering further testing and to provide a possible first
impression of the mode of action of a substance.
Based on the
reasonable vapour pressure of11hPa
at 20°C a saturated vapor concentration of 41mg/l can be calculated. Up
to this maximally achievable vapor concentration inhalation of trioxane
is predominantly as a vapor. Due to thereasonablewater
solubility of 172 g/l and the low/moderate log P value of -0.5 a good
transport via the alveolar and capillary membranes can be anticipated.
Although for considerably soluble vapors the deposition pattern differs
from lipophilic substances in that the hydrophilic are effectively
removed from the air in the upper respiratory tract. The rate of
systemic uptake may therefore be limited by active transport out of the
deposition region with the mucus and subsequent swallowing (Guidance
on information requirements and chemical safety assessment Chapter R.7c:
Endpoint specific guidance).
Summarized it can be anticipated that trioxane is readily absorbed from
the GI-tract. Concerning the metabolization of 1,3,5-trioxane it can be
hypothesized that the molecule is enzymatically hydrolysed to
formaldehyde. Formaldehyde then undergoes gradual oxidation to formic
acid and subsequently to carbon dioxide and water.Trioxane tissue
concentrations rapidly decayed and similarly elimination from the
organism was rapid. Hence no tissue accumulation can be anticipated.Excretion
is mainly as CO2 via the exhaled air and to a minor part via
Based on this toxicocinetic data it can be anticipated, that inhalation
appears to be the more sensitive route of exposure. Presumably after
oral administration a major part of the bioavailable trioxane will be
metabolized in the liver (first-pass effect).
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