Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Based on available physico-chemical properties and toxicological data of the substance
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment based on physico-chemical properties and toxicological data of the substance.

Data source

Reference
Reference Type:
other: Expert judgment
Title:
No information

Materials and methods

Objective of study:
other: Toxicokinetic assessment
Principles of method if other than guideline:
An expert assessment was made based on all data available.

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Administration / exposure

Details on study design:
A toxicokinetic assessment has been performed based on available physico-chemical properties and toxicological data of the substance.

Results and discussion

Main ADME results
Type:
absorption
Results:
Based on available physico-chemical properties and toxicological data , the oral, dermal and inhalation absorption for C12-14 alkylmorpholine is expected to be greater than 50%. For DNEL derivation purposes, absorption of 100% was assumed via all routes.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Based on available physico-chemical properties and toxicological data , the oral, dermal and inhalation absorption for C12-14 alkylmorpholine is expected to be greater than 50%. For DNEL derivation purposes, absorption of 100% was assumed via all routes.
Executive summary:

No specific toxicokinetics data is available for C12-14 alkylmorpholine. The toxicokinetic assessment is therefore based on available physico-chemical properties and toxicological data of C12-C14 alkylmorpholine.

 

The molecular weight of C12-C14 alkylmorpholine (255-284 g/mol) and the octanol-water partition coefficient (i.e., Log Kow) of 4 favors the absorption in the gastrointestinal tract. Therefore, based on the available physical/chemical properties of C12-C14 alkylmorpholine, the oral absorption is expected to be ≥ 50%. For DNEL derivation purposes a 100% oral absorption has been assumed. This is further supported by the human intestinal absorption (HIA) values which were obtained via QSAR toolbox (version 2.3). The % of HIA for all the components of C12-C14 alkylmorpholine has been modeled to be 91-93%.

 

The moderate molecular weight and its log Kow of 4 also favors the absorption of C12-C14 alkylmorpholine via the dermal route. According to the criteria given in the REACH Guidance, the MW and the log Kow requires consideration a dermal penetration of 100%. Moreover, while inhalation exposure is considered unlikely as a result of the manufacturing conditions and the low vapor pressure (i.e., 0.18 Pa) of C12-C14 alkylmorpholine, in can be assumed that once the substance is inhaled, it will become readily bioavailable. Hence, for DNEL derivation purposes and inhalatory absorption of 100% has been assumed.

 

Once systemically available, C12-C14 alkylmorpholine is expected to be readily metabolized, most likely by beta-oxidation of the carbon chain and Calkyl-N cleavage as the most likely initial reaction pathways. Excretion will occur via the urine and the bile. Due its moderate log Kow and its potential to readily metabolize into more water soluble compounds, C12-C14 alkylmorpholine may show only very little tendency to accumulate in adipose tissue. This is assessment is further supported by available biodegradability studies which show that C12-C14 alkylmorpholine is readily biodegradable.

 

 

Additionally, in the attacheddocument themolecular profiling, estimation of possible metabolism, available data and results from QSARs are compared between C12-14 alkylmorpholine and ethylmorpholine, which serves in support of additional reference to data on ethyl-morpholine made in section 7.8.1 toxicity to reproduction.

Form this can be concluded that chemical structure of C12 -C14-alkylmorpholine and Ethyl Ethyl-morpholine are similar (i.e 4-alkyl morpholine), leading to comparable molecular profiles. Estimation of possible metabolism indicates a similar profile for C12-14 alkylmorpholine and ethylmorpholine.

Also available data for human health hazard end points show comparable results.

Repeated dose studies no indication for accumulative toxicity for either C12-14-alkylmorpholine and Ethyl-morpholine. The reproduction screening study indicates no concerns for reproduction toxicity.