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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Relevant studies and literature were reviewed.

Data source

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
An assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information. The assessment is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpoint specific guidance (ECHA, November 2012)
GLP compliance:
no
Remarks:
Not relevant for assessment

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Details on the test material used in the studies assessed are presented in the respective endpoint study records.

Results and discussion

Any other information on results incl. tables

Assessment based on study results (as in endpoint study records)

Toxicokinetic Behaviour

The substance is composed as in section 1.2 of IUCLID. The substance is a piperidinediol of low molecular weight and high water solubility that does not preclude absorption. It is a non volatile solid (vapour pressure 0.000077 Pa at 25°C) of non respirable particle size and therefore inhalation exposure is not anticipated. Although the molecular weight makes dermal absorption possible, systemic availability is limited by the surface tension.

Absorption

Clear evidence of systemic effects was detected in acute and repeated dose oral toxicity studies indicating that adsorption can occur from the gastro-intestinal tract. An acute dermal toxicity study showed no such effects so there is no evidence of absorption through the skin. The substance has a low Log10Pow which might suggest poor diffusion across membranes and hence absorption, but it is highly water soluble and may have greater lipid solubility than suggested by the partition coefficient. The nitrogen group is ionisable, particularly under the acidic conditions prevalent in the stomach, so potential for absorption would be greatest from the intestine.

Distribution

Based on the physicochemical property of the substance i.e. low molecular weight coupled with very high water solubility will result in rapid absorption and fast past metabolism, therefore, distribution to peripheral tissues is limited. Distribution to the liver and metabolising cells are expected as indicated by the increased liver weight, centrilobular hepatocyte hypertrophy and cortical hypertrophy in the repeated dose oral toxicity study OECD 422.

Bioaccumulation is unlikely for a substance with such a low Log10Pow 0f 0.58, low molecular weight and high water solubility. The substance is a mild contact sensitiser and may therefore be capable of binding to proteins.

Metabolism

There is indirect evidence to indicate hepatic metabolism due to the increased liver weight, centrilobular hepatocyte hypertrophy and cortical hypertrophy identified in the repeated dose oral toxicity study, which could be associated with microsomal enzyme induction. The substance is expected to undergo redox cycle reaction catalysed by cytochrome P-450 reductase in a NADPH-dependent reduction to produced hydroxylamine derivative and nitroxide radical. The substance is known to oxidise readily, particularly at high pH and, if not already oxidised, oxidative metabolism might be expected to produce the corresponding oxy compound. In addition to the reversible redox reactions, 1,4 -Dihydroxy-2,2,6,6 -tetramethylpiperidine is consumed by recombination reactions with alkyl, alkoxyl, tyrosyl and thiyl radicals.

Excretion

Based on the low molecular weight and high-water solubility and subsequent metabolic pathway, excretion of the substance is expected to be via urine. This is supported by available data in Published literature (see attached background material). Based on the available data from the OECD 442, there is no indication of organ/tissue specific accumulation, further supportive of the rapid elimination of the substance.

Applicant's summary and conclusion

Conclusions:
The available information suggests that absorption of the test substance from the gastrointestinal tract can take place. There was no evidence for absorption via the skin. Once absorbed distribution to the liver, blood and route of excretion is indicated. Excretion via the kidneys in urine is indicated.