Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: An expert statement
Adequacy of study:
key study
Study period:
2014-11-19
Reliability:
1 (reliable without restriction)
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Radiolabelling:
no

Test animals

Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The estimated partition coefficient (log Pow=16.97) indicates that the compound is not likely to penetrate skin. However, even if dermally absorbed, its toxicity is very low. An acute dermal toxicity study revealed a LD50 > 2000 mg/kg in a limit dose test. No local irritation effects were noted in the acute dermal toxicity study, therefore testing of dermal irritation was waived. An eye irritation test with rabbits showed no eye irritation effects. In the local lymph node assay (LLNA), SIKA Hardener LI revealed sensitization potential. 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). Hydrolysis products might be absorbed to a small extend following oral application as indicated by a subchronic oral repeated dose toxicity study, which revealed a NOAEL of 300 mg/kg bw/day in female rats due to changes in spleen weights at the highest dose tested (1000 mg/kg bw/day).
Details on distribution in tissues:
Due to its high reactivity, orally ingested SIKA Hardener LI will undergo spontaneous hydrolysis upon reaching the stomach, especially as the hydrolysis reaction is acid catalysed. The portion of SIKA Hardener LI not immediately hydrolysed will, most probably, not solubilise in the stomach, due to its low solubility. Consequently, SIKA Hardener LI is not likely to cross GI-tract membranes. Taken together, absorption of SIKA Hardener LI and consequently bioavailability is rather low.
Details on excretion:
Toxicokinetic assessment of hexamethylenediamine (EC IUCLID, 2000), 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 %), feces (27 %) and respiration (20 %). Similar excretion can be assumed for all polyamine degradation products (one of the 2 decomposition products of SIKA Hardener LI is a polyamine - 3-aminomethyl-3,5,5-trimethylcyclohexylamine).

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.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Details on metabolites: The products of SIKA Hardener LI decomposition are the aldehyde 2,2-dimethyl-3-lauroyloxy-propanal and respective diamine (3-aminomethyl-3,5,5-trimethylcyclohexylamine). The aldehyde is not stable in water-based systems and further degrades, forming carbonic acid and several short-chain polar compounds. The diamine formed might also be transformed further, most likely in enzyme catalysed metabolism. Even though the SIKA Hardener LI degradation products might be absorbed and become bioavailable, they are of low toxicity. However, some effects were revealed by a subchronic oral toxicity study as mentioned above.

One of the most important pathways 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 diamine, formed by hydrolysis of SIKA Hardener LI, that reaches the body’s systemic circulation is 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 (EC IUCLID, 2000), 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 %), feces (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, a chromosome aberration test and a mouse lymphoma assay. In all three assays no significant increases in toxicity were noted, in the presence of a rodent microsomal S9-fraction.


Any other information on results incl. tables

Not applicable

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: No bioaccumulation potential based on a toxicokinetic assessment
Based on molecular structure and physical-chemical properties, bioaccumulation of SIKA Hardener LI is not likely to occur. Dermal and inhalation uptake can be practically exclued. Orally consumed hardener is very fast hydrolysed to aldehyde and diamine, in the acid environment of the stomach. 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.

Executive summary:

SIKA Hardener LI is designed to rapidly react upon contact with water, which is reflected in its properties. The hydrolysis reaction is catalysed in an acid environment. The molecular weight is 703.13 g/mol, the calculated partition coefficient logPow is 16.97, the estimated water solubility is 1.065E-13 mg/L and the experimental determined vapour pressure is 0.00138 Pa at 25°C.

Based on the low vapour pressure corresponding to a low volatility potential, inhalation of the substance as a vapour to a high extend is unlikely.

The estimated partition coefficient indicates that the compound is not likely to penetrate skin. However, even if dermally absorbed, its toxicity is very low. An acute dermal toxicity study revealed a LD50 > 2000 mg/kg in a limit dose test. No local irritation effects were noted in the acute dermal toxicity study, therefore testing of dermal irritation was waived. An eye irritation test with rabbits showed no eye irritation effects. In the local lymph node assay (LLNA), SIKA Hardener LI revealed sensitization potential. 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).

Hydrolysis products might be absorbed to a small extend following oral application as indicated by a subchronic oral repeated dose toxicity study, which revealed a NOAEL of 300 mg/kg bw/day in female rats due to changes in spleen weights at the highest dose tested (1000 mg/kg bw/day). Due to its high reactivity, orally ingested SIKA Hardener LI will undergo spontaneous hydrolysis upon reaching the stomach, especially as the hydrolysis reaction is acid catalysed. The portion of SIKA Hardener LI not immediately hydrolysed will, most probably, not solubilise in the stomach, due to its low solubility. Consequently, SIKA Hardener LI is not likely to cross GI-tract membranes.

Taken together, absorption of SIKA Hardener LI and consequently bioavailability is rather unlikely. However, some effects were revealed by a subchronic oral toxicity study as mentioned above. The products of SIKA Hardener LI decomposition are the aldehyde 2,2-dimethyl-3-lauroyloxy-propanal and respective diamine (3-aminomethyl-3,5,5-trimethylcyclohexylamine). The aldehyde is not stable in water-based systems and further degrades, forming carbonic acid and several short-chain polar compounds. The polyamine formed might also be transformed further, most likely in enzyme catalysed metabolism. Even though the SIKA Hardener LI degradation products might be absorbed and become bioavailable, they are of low toxicity. One of the most important pathways 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 polyamine, formed by hydrolysis of SIKA Hardener LI, that reaches the body’s systemic circulation is 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 (EC IUCLID, 2000), 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 %), feces (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 25μg/m3. In a second human inhalation study and exposure to 30μg/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, a chromosome aberration test and a mouse lymphoma assay. In all three 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 LI and its limited stability in water-based systems, bioaccumulation is not likely to occur. Orally consumed hardener is most rapidly hydrolysed to aldehyde and diamine, 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.