Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Qualifier:
no guideline required
Principles of method if other than guideline:
Expert statement
GLP compliance:
not specified
Details on test animals and environmental conditions:
Not applicable
Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applcable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable
Preliminary studies:
Not applicable
Details on absorption:
The estimated partition coefficient (logPow = 14.22) 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 sensitisation study. In the skin irritation study, using rabbits, no local effects or systemic toxicity were noted, following topical application of Sika Härter LH. 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 IUCLID-data).
Details on distribution in tissues:
Due to its high reactivity, orally ingested Sika Hardener LH will undergo spontaneous hydrolysis upon reaching the stomach, especially as the hydrolysis reaction is acid catalysed. The portion of Sika Härter LH not hydrolysed immediately will, most probably, not solubilise in the stomach, due to its low solubility. Consequently, Sika Hardener LH is not likely to cross GI-tract membranes. Taken together, absorption of Sika Hardener LH and consequently bioavailability is rather unlikely.
Details on excretion:
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 the 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.
Metabolites identified:
yes
Details on metabolites:
The products of Sika Hardener LH decomposition are the aldehyde 2,2-dimethyl-3-lauroyloxy-propanal and respective polyamine (Hexamethylenediamine). 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 catalysed metabolism. Even though the Sika Härter LH degradation products might be absorbed and become bioavailable, they are of low toxicity .

One of the most important pathway of aldehyde metabolism is oxidation to carboxylic acids by aldehyde dehydrogenases (Vasiliou et al., 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.

Any polyamines, formed by hydrolysis of Sika Hardener LH, 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 likely to be followed by 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 the 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.

It is unlikely that metabolism will render the parent compound nor 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 unlikely.

Not applicable

Conclusions:
Based on the reactive nature of Sika Härter LH 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 rather unlikely. Absorbed or bioavailable degradation products are probably excreted, either in original form or further metabolised, prior to elimination via urine or bile. Formation of toxic metabolites is unlikely, based on the results of the sub acute toxicity study and two in vitro studies using isolated S9 fractions. Based on the results of the sub chronic toxicity study with the hydrolysis product Aldehyde L the target organ seems to be the spleen. However, spleen alteration were fully reversible with except of spleen weight indicating rapid excretion and no potential for bioaccumulation.

Executive summary:

SIKA Hardener LH rapidly hydrolyses upon contact with water. Further, the hydrolysis reaction is catalysed in an acid environment. Calculated partition coefficient logPow is 14.22 and estimated water solubility is 5.5E-11 mg/L.

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 sensitisation study. In the skin irritation study, using rabbits, no local effects or systemic toxicity were noted, following topical application of Sika Hardener LH. 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 IUCLID-data).

Due to its high reactivity, orally ingested Sika Hardener LH will undergo spontaneous hydrolysis upon reaching the stomach, especially as the hydrolysis reaction is acid catalysed. The portion of Sika Hardener LH not hydrolysed immediately will, most probably, not solubilise in the stomach, due to its low solubility. Consequently, Sika Hardener LH is not likely to cross GI-tract membranes. Taken together, absorption of Sika Hardener LH and consequently bioavailability is rather unlikely.

The products of Sika Hardener LH decomposition are the aldehyde 2,2-dimethyl-3-lauroyloxy-propanal and respective polyamine (Hexamethylenediamine). 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 catalysed metabolism. Even though the Sika Hardener LH degradation products might be absorbed and become bioavailable, they are of low toxicity .

One of the most important pathway of aldehyde metabolism is oxidation to carboxylic acids by aldehyde dehydrogenases (Vasiliou et al., 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.

Any polyamines, formed by hydrolysis of Sika Hardener LH, 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 likely to be followed by 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 the 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.

It is unlikely that metabolism will render neither the parent compound nor 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 unlikely.

Based on the reactive nature of Sika Hardener LH 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. Thus, absorption of SIKA Hardener LH is most unlikely. Although the results of the sub chronic toxicity reveal alterations in the spleen in females in form of macroscopically enlargement associated with increases in spleen weight accompanied by splenic hyperplasia after exposure with Sika Hardener LH, this effect is most likely attributed to the hydrolysis product Aldehyde L (see disseminated dossier published on the ECHA homepage, submitted by Incorez Ltd.). Splenic alterations were fully reversible after exposure with SIKA Hardener LH or Aldehyde L; however, changes in the spleen weight were detected at the end of the recovery period. 

Even though the degradation products might be absorbed and become bioavailable, toxicity is low bioconcentration rather unlikely. Absorbed or bioavailable degradation products are probably excreted, either in original form or further metabolised, prior to elimination via urine or bile. Formation of toxic metabolites is unlikely, based on the results of the sub acute toxicity study and two in vitro studies using isolated S9 fractions as well as the reversibility of the spleen alterations in the sub chronic toxicity study.

 

 

Description of key information

Based on the reactive nature of Sika Hardener LH 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 rather unlikely. Absorbed or bioavailable degradation products are probably excreted, either in original form or further metabolised, prior to elimination via urine or bile. Formation of toxic metabolites is unlikely, based on the results of the sub acute toxicity study and two in vitro studies using isolated S9 fractions. Based on the results of the sub chronic toxicity study with the hydrolysis product Aldehyde L the target organ seems to be the spleen. However, spleen alteration were fully reversible with except of spleen weight indicating rapid excretion and no potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

General

Sika Hardener LH belongs to a class of polyaldimine compounds used as hardeners for polyurethane moisture hardening preparations. On contact with water, the hardening process is initiated and the hardener rapidly hydrolysed. Hydrolysis products formed are the aldehyde 2,2-dimethyl-3-lauroyloxy-propanal and corresponding polyamine Hexamethylenediamine. The hardener and polyurethane mass react and become chemically bound in the polymer matrix, irreversibly integrating the polyamine.

Due to the compounds use, Sika Hardenerr LH has a very limited stability in water, as it needs to rapidly react upon contact with water. Thus, determination of its partition coefficient or water solubility is not technically feasible. The theoretical partition coefficient and water solubility ranges were calculated, taking the varying oligomere chain lengths into account.

Toxicokinetic assessment

Based on the reactive nature of Sika Hardener LH 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 rather unlikely. Absorbed or bioavailable degradation products are probably excreted, either in original form or further metabolised, prior to elimination via urine or bile. Formation of toxic metabolites is unlikely, based on the results of the sub acute toxicity study and two in vitro studies using isolated S9 fractions. Based on the results of the sub chronic toxicity study with the hydrolysis product Aldehyde L the target organ seems to be the spleen. However, spleen alteration were fully reversible with except of spleen weight indicating rapid excretion and no potential for bioaccumulation.