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Intraperitoneal application:

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 bw).

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.

Oral application:

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).

Dermal permeability can be estimated by the molecular weight, the water solubility and the logPow of a substance. For trioxane the moderate water solubility of 172 g/l (at 20°C) is facilitating a good dissolution into the surface moisture of the skin, whereas the low/moderate logPow of -0.5 will limit the potential for dermal permeation of the dissolved substance. This can be predicted by in silico equations (e.g. DERMWIN v2.00). For trioxane with a molecular weight of 90.08 g/mol the dermal permeability coefficient (Kp) was calculated as 0.000228 cm/hr indicating a very low dermal uptake.

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 urine.

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).