Poly[oxy(methyl-1,2-ethanediyl)], .alpha.-[2-[[2,2-dimethyl-3-[(1-oxododecyl)oxy]propylidene]amino]methylethyl]-.omega.-[2-[[2,2-dimethyl-3-[(1-oxododecyl)oxy]propylidene]amino]methylethoxy]-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Principles of method if other than guideline:

Expert statement

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

479-940-2

EC Name:

-

Cas Number:

613246-75-6

Molecular formula:

NA: Multi-const. substance

IUPAC Name:

16-(dodecanoyloxy)-2,2,5,8,12,15,15-heptamethyl-7,10-dioxa-4,13-diazahexadeca-3,13-dien-1-yl dodecanoate

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

All toxicokinetic analyses have to consider that Sika Hardener LJ is designed to rapidly react upon contact with water. Further, the hydrolysis reaction is catalysed in an acid environment. Sika Hardener LJ is a reaction mixture of poiyaldimine, with varying chain length. Calculated logPow values and water solubility for Sika Hardener LJ range from 13.67 to 12.96 and from 2.1E-10 mg/L to 5.6E-13 mg/L, respectively.

The estimated partition coefficient indicates that the compound is not likely to penetrate skin. However, even if dermally absorbed, its toxicity is very low. Although no acute dermal toxicity study was carried out, the compound was assessed in a skin irritation and skin sensitization study. The skin irritation study used rabbits and no local effects or systemic toxicity was noted, following topical application of Sika Hardener LJ. A guinea pig maximisation test did not reveal any signs of toxicity either and the compound was classified a non-sensitiser.
Furthermore, the aldehyde hydrolysis product did not cause any systemic toxicity, following dermal application (LD50 > 2000 mg/kg bw) nor did any of the polyamines formed (LD50 > 2000 mg/kg bw, BASF correspondence and lUCLID-data). Due to its high reactivity and limited stability in water-based systems, orally ingested Sika Hardener LJ will undergo spontaneous hydrolysis upon reaching the stomach, especially as the
hydrolysis reaction is acid catalysed. The portion of Sika Hardener LJ not hydrolysed immediately will, most probably, not solubilize in the stomach. Consequently, Sika Hardener LJ is not likely to cross GI-tract membranes. Taken together, absorption of Sika Harter LJ and consequently bioavailability are highly unlikely.
The products of Sika Hardener LJ decomposition are the aldehyde 2,2-dimethyI-3-lauroyloxy- propanal and respective polyamine (Polyetheramine D 230). The aldehyde is not stable in water-based systems and further degrades forming carbonic acid and several short-chain polar compounds. The polyamines formed might also be transformed further, most likely in enzyme catalyzed metabolism. Even though the degradation products might be absorbed and become bioavailable, they are of low toxicity.

Details on excretion:

Any polyamines formed by hydrolysis of Sika Hardener LJ that reach the body's systemic circulation are probably either excreted in unchanged form or metabolised by the cytochrome P450 system or by amine oxidases. Phase I metabolism of polyamines is followed by further conjugation of degradation products in phase II metabolism, possibly rendering molecules even more polar. Likely conjugation compounds are glycine and glutamine, preceding the metabolites eventual elimination in urine or bile.
Toxicokinetic assessment of hexamethylenediamine, used as a model compound, revealed that the amine is rapidly distributed systemically following i.v. administration to rats, and completely excreted within 72 hours, via urine (47 %), faces (27 %) and respiration (20 %). Similar excretion can be assumed for all polyamine degradation products. Excretion analysis in humans following oral administration, using the same model compound hexamethylenediamine, revealed that more than 90 % is eliminated in urine, during the first 10 hours post administration, either unchanged or metabolised to 6-aminohexanoic acid. A human inhalation study revealed that 90 % were eliminated within the first 28 hours following exposure to 25 µg/m3. In a second human inhalation study and exposure to 30 µg/m3, 90 % hexamethylenediamine was eliminated via the urine within the first three hours. For both human inhalation studies the renal half-life of hexamethylenediamine was determined to be 1.4 hours and 1.2 hours, respectively. A similar excretion pattern can be assumed for all
polyamine degradation products in humans.

Metabolite characterisation studies

Details on metabolites:

One of the most important pathway of aldehyde metabolism is oxidation to carboxylic acids by aldehyde dehydrogenases (Vasiliou et al.t 2000). The enzymes involved in these detoxification reactions most probably belong to the category of aldehyde dehydrogenases, known to be relatively substrate unspecific, but effective in protecting organisms from potentially harmful xenobiotics (Sladek, 2003). Other phase I metabolic reactions may include cytochrome P450 mediated transformations such as aldehyde reductions or aldehyde scissions. Following phase I metabolic reactions or chemical decomposition, the formed metabolites are rendered more polar by phase II metabolism. Most likely the carboxylic acid metabolites are ultimately conjugated with glycine or glutamine and excreted in urine or bile.
It is unlikely that metabolism will render the parent compound or its degradation products more toxic. This assumption is supported by results obtained in an in vitro Ames test and a chromosome aberration test. In both assays no significant increases in toxicity were noted, in the presence of a rodent microsomal S9-fraction. This clearly indicates that formation of reactive metabolites is rather unlikely.

Applicant's summary and conclusion

Conclusions:

Based on the reactive nature of Sika Hardener LJ and its limited stability in water-based systems, bioaccumulation is not likely to occur. Orally consumed hardener is most rapidly hydrolysed to aldehyde and polyamine, with the reaction being acid catalysed. Even though the degradation products might be absorbed and become bioavailable, toxicity is low and bioconcentration unlikely. Absorbed or bioavailable degradation products are probably excreted, either in original form or further metabolized, prior to elimination via urine or bile. Formation of toxic metabolites is usually, based on the results of the sub-acute toxicity study and two in vitro studies using isolated S9 fractions.