Dihexyl fumarate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

assessment of toxicokinetic behavior

Type of information:

other: In accordance with REACH Annex VIII (8.8) 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

Study period:

The assessment was conducted in January 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Relevant studies were reviewed with a view to fulfilling the requirements of Annex VIII (8.8).

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

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

Remarks:

Not relevant for assessment

Test material

Test material information

Constituent 1

Reference substance name:

Dihexyl fumarate

EC Number:

242-833-4

EC Name:

Dihexyl fumarate

Cas Number:

19139-31-2

Molecular formula:

C16H28O4

IUPAC Name:

dihexyl fumarate

Results and discussion

Any other information on results incl. tables

Toxicokinetic Behaviour:

The substance is a powder with a molecular weight of 284.391 g/mol.

The substance has a low vapour pressure (3 x 10-2 Pa at 25°C), low melting point (10°C), is not highly flammable and is not an explosive or oxidising. The substance is considered to be of low-volatility and therefore inhalation is not a significant route of exposure.

 

The substance has a high log octanol/water partition coefficient (Log Pow > 6) and low water solubility (0.15 mg/L). Hydrolysis study identifies t1/2 to be 16-34 days between pH 4 and 7 at 25°C.

 

There were no signs of toxicity in acute oral and dermal toxicity studies.

 

A 28-day repeated dose toxicity study, reproductive toxicity screening study (and associated 14-day range finding study) showed no significant evidence of absorption.

 

The substance is not a skin irritant or skin sensitiser.

 

The substance was non-mutagenic in bacteria in either the absence or presence of an auxiliary metabolising system, and was non-mutagenic in mammalian cells in vitro (L5178Y mouse lymphoma cell line) in either the absence or presence of an auxiliary metabolising system. However in mammalian cells in vitro (human lymphocytes) the test item was determined to be clastogenic. The response was due to mainly break-type aberrations which may be induced by a cytotoxic mechanism rather than a genotoxic mechanism and, therefore, have reduced biological relevance. In the MLA study however, no genotoxic activity was recorded in the any of the exposure conditions. Since in an MLA study the test cultures undergo a 48-hour expression period prior to plating out for viability and expression of mutagenicity, during this expression period any mutagenic response that induces high levels of toxicity in the cells results in cell death due to lowered viability. In the chromosome aberration data, the lack of an expression period results in the presence of mutagenic events that would most likely be non-viable if the cultures were maintained for a greater period of time.

 

Absorption:

Inhalation is not considered to be a significant route of exposure based on the substance being non-volatile.

 

The molecular weight of the substance does not preclude absorption from the gastrointestinal tract following oral ingestion. However, the log Pow (>6) and low water solubility (0.15 mg/L) of the substance suggest that absorption would be limited from the gastrointestinal tract following oral ingestion. Any absorption that occurs for this substance may be by micellular solubilisation.

 

Limited absorption from the gastrointestinal tract following oral ingestion is supported by the results from oral toxicity studies. An acute oral toxicity study showed no evidence of systemic toxicity. In an oral repeated dose toxicity study (OECD 422) there was no significant evidence of absorption. The only effects observed in the study were determined not to be treatment related, or the magnitude of these differences from controls were minimal and there were no corroborative microscopic findings, and the effects were considered not to be of toxicological importance.

The results from a toxicity reproductive toxicity screening study (and 14-day range finding study) also show limited evidence of absorption.

 

The log Pow and low water solubility of the substance suggest that dermal absorption will be low. This is supported by the results of an in-vivo skin irritation study and skin sensitisation studies, which showed no evidence of systemic toxicity.

 

The substance is not a skin irritant so significant damage to the skin surface should not occur to enhance penetration.

 

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

 

Distribution:

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

 

Significant systemic distribution was not evident from the repeated dose toxicity studies (28-day toxicity study and reproductive toxicity screening study).

 

The lack of skin sensitization response would suggest the substance does not bind to circulatory proteins.

 

The partition coefficient (Log Pow >6) would suggest the substance has some limited affinity to accumulate in fatty tissues.

 

Metabolism:

The results of the repeated dose toxicity study did not show evidence to indicate any substance influenced hepatic metabolism.

 

The results of the genotoxicity assays have shown that genotoxicity is neither enhanced or diminished in the presence of a metabolising system.

 

Excretion:

There is no evidence to indicate the route of excretion but poorly water-soluble products are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this substance. Any substance that is not absorbed will be excreted in the faeces.

 

Applicant's summary and conclusion

Conclusions:

The available information suggests that absorption of the test substance from the gastrointestinal tract and absorption via the skin will be limited. Widespread distribution of any absorbed substance is not anticipated. Any substance absorbed may have some potential to accumulate in fatty tissues. Biliary excretion may well be the significant route of excretion. There is no evidence to suggest that the test substance may be metabolised.