4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement based on physico-chemical and toxicological data

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

absorption

Qualifier:

no guideline followed

Principles of method if other than guideline:

expert statement based on physico-chemical and toxicological data according to REACH Guidance R.7

GLP compliance:

no

Details on absorption:

At >1000 g/L at 20°C, ZK 39294 is readily soluble in water and not very lipophilic, which is reflected in the octanol/water partition coefficient (log Pow) of -0.07 at 25°C.
Due to this low fat solubility, absorption of the substance through the outer skin and mucous membranes is considered to be rather low.
The substance is expected to be absorbed unchanged from the gastrointestinal tract, however only to a rather small extent. This is indicated by the results of the 28-day study in rats, in which no findings were reported up to 40 mg/kg daily. Even the daily administration of 200 mg/kg over 4 weeks caused only minor impairment of the general condition, which indicates that the limit of general tolerability has been reached.
The test results for mutagenicity are negative. It is assumed that either rapid deactivation of the epoxide function by epoxide hydrolase or the absence of cellular absorption is responsible for this result.
The vapor pressure with a value of 30.5 Pa (20°C) is rather high, Thus, absorption by inhalation must be expected.
Because of its low lipophilicity, the substance will most likely be distributed primarily in the extracellular space and hardly in organs and tissues.
Because of the small molecular size and the high hydrophilicity, predominantly renal excretion is to be expected. In principle, possible metabolic reactions, such as hydroxylation and various conjugations may further increase the water solubility and subsequently stimulating the renal excretion.
No toxicologically significant systemic effects of ZK 39294 after single or multiple oral or single dermal administration were detected. These results indicate either a lack of adverse effects based on low bioavailability or a good systemic availability and tolerability, the latter one can be explained by a rapid deactivation of the epoxide function in first place.

Conclusions:

Treatment with the test item does not result in a major impairment of the general condition in the available toxicological data. These results in correlation with its physico-chemical properties rather indicate a reduced bioavailability via the gastrointestinal tract and the skin. However, a rapid metabolism due to its hydrophilic structure, i.e. the epoxid moiety can also not be excluded. Based on the high vapour pressure also absorption via inhalation may be possible.

Description of key information

expert statement based on physico-chemical and toxicological data.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Treatment with the test item does not result in a major impairment of the general condition in the available toxicological data. These results in correlation with its physico-chemical properties rather indicate a reduced bioavailability via the gastrointestinal tract and the skin. However, a rapid metabolism due to its hydrophilic structure, i.e. the epoxid moiety can also not be excluded. Based on the high vapour pressure also absorption via inhalation may be possible.