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Description of key information

A theoretical assessment of the toxicokinetics of di-TMP is made, based on the molecular structure and information from toxicity studies. The theoretical assessment is supported by the results of an in vitro study of absorption.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

A theoretical assessment of the toxicokinetics of di-TMP is made, based on the molecular structure and information from toxicity studies. The theoretical assessment is supported by the results of an in vitro study of absorption.

Theoretical assessment indicates rapid and extensive absorption and distribution; rapid metabolism and excretion are likely to limit systemic exposure and toxicity. No bioaccumulation is predicted.

Absorption

Oral absorption of di-TMP is predicted based on the substance molecular size, solubility, chemical structure and on the basis of experience with other polyol substances. The molecule satisfies Lipinski's rule of 5 (OECD QSAR Toolbox). Studies of oral toxicity do not provide any direct indication of gastrointestinal absorption. Signs of toxicity in the acute oral toxicity studies are limited to non-specific effects at excessively high dose levels. A 28-day rat study performed with di-TMP reports renal findings in all treated groups; however the lack of consistency between the sexes, the absence of a clear dose-response relationship and nature of findings do not indicate a relationship to treatment. The results of an in vitro study performed using everted rat intestinal sacs

indicates that di-TMP is well absorbed.

In the absence of data, absorption following inhalation exposure is assumed to be extensive.

The dermal absorption of di-TMP is likely; the extent of dermal absorption is likely to be less than oral absorption.  In the absence of any data, the extent of oral and dermal absorption is assumed to be comparable.

Distribution

No data are available; findings from repeated dose toxicity studies do not indicate any specific targets of toxicity. Rapid and extensive distribution of absorbed di-TMP and its metabolites can be predicted based on knowledge for related substances. di-TMP is likely to be rapidly absorbed and subject to extensive hepatic metabolism resulting in the renal excretion of water-soluble metabolites.  The systemic distribution of di-TMP is therefore likely to be limited by its metabolism and excretion.

Metabolism

Hydrolysis of the ether linkage and sequential oxidative metabolism of the hydroxy groups present in the molecule is predicted, based on known metabolic reactions and the elucidated pathways for other alcohol compounds. There are no additional chemical groups known to be susceptible to mammalian metabolism. Theoretical assessment (OECD QSAR toolbox) predicts a total of twenty hepatic metabolites produced by hydrolysis and/or alcohol oxidation form the corresponding aldehyde and carboxylic acid. Rapid hepatic metabolism is indicated, which will facilitate excretion and limit systemic exposure and toxicity.

Excretion

Rapid and extensive renal excretion of di-TMP and/or its metabolites is likely, with no potential for bioaccumulation based on chemical properties. Findings are consistent with the low toxicity seen in the repeated-dose toxicity studies.