Reaction mass of N-(hydroxymethyl)hexadecan-1-amide and N-(hydroxymethyl)stearamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Toxicological assessment

Type of information:

other: Toxicological assessment

Adequacy of study:

key study

Study period:

December 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The statement is performend through an expert of toxicology referring to the available data.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of N-(hydroxymethyl)hexadecan-1-amide and N-(hydroxymethyl)stearamide

EC Number:

911-553-0

Molecular formula:

not applicable

IUPAC Name:

Reaction mass of N-(hydroxymethyl)hexadecan-1-amide and N-(hydroxymethyl)stearamide

Test material form:

solid: particulate/powder

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

dermal 10 %, inhalation 100 %, oral 100 %

Main ADME results 2

Type:

distribution

Results:

Very low water solubility, very lipophilic. A high distribution volume is possible.

Main ADME results 3

Type:

metabolism

Results:

The resulting Fatty acid Amide should be subject to fatty acid metabolism. The present Hydroxy and Amine Group is target for Phase II metabolism

Main ADME results 4

Type:

excretion

Results:

renal and excretion by faeces is possible. Excretion by exhalation does not seem to be relevant.

Any other information on results incl. tables

Estimation of the toxicokinetic behavior of N-(hydroxymethyl)stearamide

 

Data from in vivo studies, which were designed to identify the toxicokinetic properties of the substance, are not available.

This means, that absorption, distribution, metabolism and excretion (ADME) can only be derived from available physical-chemical data.

To estimate the toxicokinetic properties of the substance the following information was considered (cited from IUCLID6 data file, section 4):

Parameter	Value used for CSR
Molecular weight	314 g/mol
Melting point	156 °C (calculated, Gold and Ogle method) 104 – 111 °C (experimental)
Boiling point	463 °C (calculated) 146.9 °C (experimental)
Density	1.0282
Vapour pressure	1.29 E-08 mm Hg (calculated, Mackay method) 0.00021 Pa
Partition coefficient n-octanol/water (log POW)	> 6.5
Water solubility	40 µg/L
pH	Not relevant
pKa	14.4 (calculated)
Particle size	43.6 µm

 

Absorption:

Based on above data the substance is not likely to be absorbed through the skin in relevant amounts. The log P_OWis outside the thresholds for dermal absorption, however the molecular weight indicates a “small molecule”. For exposure assessments a default value of 10 % of absorption after dermal exposure may be appropriate. (molecular weight < 500 g/Mol, but log Pow is out of range -1 < log P_OW< 4, see EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRETORATE-GENERAL: Guidance Document on Dermal Absorpiton Sanco/222/2000 rev. 7 19 March 2004).

 

The uptake after direct inhalation of the substance may be of medium relevance due to the mean diameter of particles, which is in the range of particles reaching the thoraical region, however exposure to the alveolar region is unlikely (threshold 15 µm). Uptake by inhalation after evaporation is unlikely. The substance is a solid at room temperature with a very low vapour pressure and a boiling point well above 100 °C. For exposure assessments a default value of 100 % of absorption via inhalation may be appropriate.

 

The absorption after oral ingestion cannot be calculated due to lack of data; by default an absorption of 100 % may be appropriate, until specific data will be available, although such a high absorption is rather unlikely.

 

Distribution:

A very low solubility is determined. By the chemical structurer the substance is very lipophilic and Protein binding can occur, therefore a high distribution volume may result. Distribution to specific organs should depend on the blood flow rate of the organs with, kidney and liver as potentially primary targets. Crossing of membrane barriers like the Blood/Brain barrier seems unlikely giving the rather high molecular weight.

 

Metabolism and Excretion:

The present N-methylol functionality is known to release Formaldehydein aqueous media (Ashby, et al. (1985). Chloracetamide-N-metholol: an example of an in vitro and in vivo clastogen which is non-mutagenic to Salmonella. Mutat. Res.156, 19-32.; Coley, et al. (1995). The role of the N-(hydroxymethyl)melamines as antitumour agents: mechanism of action studies. Biochem. Pharmacol. 49, 1203-1212.).

The resulting Fatty acid Amide should be subject to fatty acid metabolism.

The present Hydroxy and Amine Group is target for Phase II metabolism (e.g. glucuronation, acetylation …).

 

All of these reactions lead to water soluble metabolites which are subject to urinary excretion, which may be the most relevant way of excretion for this substance.

Another relevant pathway for excretion may be by feces, especially for the fraction, which has not been absorbed in the gastrointestinal tract after oral uptake.

Excretion by exhalation does not seem to be relevant.

Potential for Bioaccumulation:

Due to the high log Pow and uncertainties in metabolism a low potential for Bioaccumulation is cannot be excluded.

Applicant's summary and conclusion

Executive summary:

Absorption: Dermal 10 %, inhalation 100 %, oral 100 %.

Distribution: A high distribution volume is possible.

Metabolism: The resulting Fatty acid Amide should be subject to fatty acid metabolism.  The present Hydroxy and Amine Group is target for Phase II metabolism.

Excretion: Renal and excretion by faeces is possible. Excretion by exhalation does not seem to be relevant.