Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
assessment of toxicokinetic behavior
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: toxicokinetic assessment
Title:
Unnamed
Year:
2020

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) 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, June 2017)
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Results and discussion

Any other information on results incl. tables

The substance is a substituted sorbitol, molecular weight 414. It is an involatile solid at room temperature, with a vapour pressure of 0.0053 Pa at 25°C and has no hazardous physico-chemical properties. The substance has a water solubility of <0.438 mg/L, and has a log Pow of <1.6.

The particle size distribution of the substance (powder form) was determined as follows: 10 vol % of substance passed through for 2.10 μm, 50 vol % of substance passed through for 5.50 μm, 90 vol % of substance passed through for 28.0 μm

The assessment is based on study data on the substance itself and study data read-across from two structurally similar substances (EC 413-110-2 and EC 402-950-5).

 

There were no signs of toxicity/adverse effects following single or repeated dose oral administration, or following acute dermal administration.

The substance was non-mutagenic in bacteria, non-clastogenic in mammalian cells in vitro (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 classified as a skin sensitiser or irritant.

Absorption

Given the particle size of the material and low volatility of the substance, inhalation is not considered to be a significant route of exposure.

 

The molecular weight and log Pow of the substance suggest that the substance may have some potential for absorption following oral administration but its low water solubility suggests limited potential for absorption for GI tract.. The results of oral toxicity studies on the substance (acute oral toxicity study and 90 day repeat-dose toxicity oral feed study) show very limited evidence to support significant gastric absorption of the substance.

Repeated dose toxicity studies (OECD 421 and OECD 415) on structurally similar substances EC 413-110-2 and EC 402-950-5 also showed limited evidence to support significant gastric absorption of the substance.

Absorption via the skin is expected to be limited due to the physical nature of the substance (dry solid) and molecular weight. The log Pow (<1.6) is expected to limit dermal absorption and the low water solubility indicates dermal uptake will be low.

No signs of systemic toxicity or local irritation were observed in an acute dermal toxicity studies and skin sensitisation studies conducted on the substance and on strucutrally simular substances EC 413-110-2 and EC 402-950-5), indicating significant dermal absorption had not occurred.

The results of the acute and repeated dose toxicity studies show no significant evidence of toxicity there is little to confirm that there has been significant absorption of the test item; or the test item is not inherently toxic.

Distribution

The water solubility of the substance suggests potential for distribution of the substance could be limited. There is no significant evidence to suggest widespread distribution of the test material will occur.

Significant systemic distribution was not evident from the repeated dose study available on the substance (90 -day repeat-dose toxicity oral feed study).

Significant systemic distribution was also not evident from the repeat dose studies available on the structurally similar substances (EC 413-110-2 and EC 402-950-5)

, which are slightly more water soluble so may be anticipated to have shown higher distribution.

The negative responses in a skin sensitisation studies 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 (<1.6).

Metabolism

The results of the repeated dose studies did not show evidence to indicate any significant 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

Based on the molecular weight of the substance and water solubility, it is unlikely that urinary excretion via the kidney will be the main route of extrection. Following oral ingestion, any test item that is not absorbed is likely to be excreted in the faeces.

 

Applicant's summary and conclusion

Conclusions:
The available evidence from studies shows no significant evidence of toxicity and there is little to confirm that there has been significant absorption of the test item; or the test item is not inherently toxic. The study evidence suggests any substance absorbed may not be significantly systemically distributed and there is considered to be low potential for accumulation in fatty tissues. There is limited evidence to suggest that the substance may be metabolised. Following oral ingestion, any test item that is not absorbed is likely to be excreted in the faeces.