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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: 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 were reviewed with a view to fulfilling the requirements of Annex VIII (8.8.1).

Data source

Reference
Reference Type:
other: an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information.
Title:
Unnamed
Year:
2014

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(2,6-bis(4-tolyl)-1,3-dioxano(5,4-d)-1,3-dioxan-4-yl)ethane-1,2-diol
EC Number:
402-950-5
EC Name:
1-(2,6-bis(4-tolyl)-1,3-dioxano(5,4-d)-1,3-dioxan-4-yl)ethane-1,2-diol
Cas Number:
87826-41-3
Molecular formula:
C22 H26 O6
IUPAC Name:
(1R)-1-[(4R,4aR,8aS)-2,6-bis(4-methylphenyl)-hexahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl]ethane-1,2-diol

Results and discussion

Any other information on results incl. tables

The substance is a substituted sorbitol, molecular weight 386.5. It is an involatile solid at room temperature. 11.5% of the particles are smaller than 100 μm, 3.9% are smaller than 10 μm and less than 0.6% are smaller than 5.5 μm. The substance is poorly water soluble (1.5 mg/L), is reasonably stable in water solution at pH 4 (half life ~8.3 d), 7 and 9 (stable) and has a log Pow of 2.51.

 

There were no signs of toxicity following single or repeated dose oral administration, following inhalation exposure and following dermal administration.

The substance was non-mutagenic in bacteria, non-clastogenic in mammalian cells in vitro (human lymphocytes and CHL) and non-mutagenic in mammalian cells in vitro (L5178Y mouse lymphoma cell line) in either the absence or presence of an auxiliary metabolising system.

The substance is not a skin sensitiser or irritant.

Absorption

Given the particle size of the material and low volatility of the substance (vapour pressure 4.9 x 10-6 Pa at 25°C), inhalation is not considered to be a significant route of exposure.

 

The molecular weight and low water solubility suggest that the substance is unlikely to be significantly absorbed when administered orally. The toxicity information also suggests that this may be the case as results of the acute oral study and repeat dose oral studies (28 -day, 90 -day oral feed and 1 -generation reproduction study) show very limited evidence to support the gastric absorption of the substance.

Absorption via the skin is expected to be very limited due to the molecular weight, log Pow and low water solubility. No signs of systemic toxicity or local irritation were observed in acute dermal and skin irritation studies.

Distribution

There is no significant evidence to suggest widespread distribution of the test material will occur. This is supported by the low water solubility of the substance.

Significant systemic distribution was not evident from the repeat dose studies (28-day, 90-day and 1-generation reproduction study).

The negative response in a skin sensitisation study suggests the substance will not bind to carrier proteins in the circulatory system, which would facilitate distribution.

 

The likelihood of substantial accumulation of the substance in fatty tissues is low based on the substances log Pow (2.51).

Metabolism

Prediction of the metabolism of this substance is speculative. There are two hydroxygroups on the sorbitol that could be conjugated with glucuronic acid and/or sulphate. The p-methyl groups on the tolyl moieties may be oxidised to the alcohol and thence to the acid, and the acid could be conjugated.

 

The results of the repeated dose studies did not show evidence to indicate any test item influenced hepatic metabolism.

The results of the genotoxicity assays have shown that gentoxicity is neither enhanced or diminished in the presence of metabolic activation.

Excretion

There is no evidence to indicate the route of excretion but poorly water soluble substances are not favourable for urinary excretion. Therefore, biliary excretion may well be a significant route for this substance.

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The available information suggests that absorption of the substance will be limited both orally (from the gastrointestinal tract) and dermally via the skin. Any substance absorbed would not be anticipated to be significantly systemically distributed but there is considered to be low potential for accumulation in fatty tissues. There is limited evidence to suggesting that the substance may be metabolised.