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Description of key information

Based on the physico-chemical properties, the oral absorption potential of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcoholsvia micellar solubilisation is expected to be high, while the dermal absorption potential cannot be excluded and the inhalation absorption potential is predicted to be low. Moreover, due to the lipophilic character (log Pow > 7.97) a bioaccumulation potential cannot be excluded. However, the OECD QSAR toolbox prediction indicates that the test substance may be metabolised within the body in phase I-reactions. Further metabolism in phase II reactions are expected. The predicted metabolites are probably excreted via faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols is an UVCB substance and three representative constituents are presented in Table 1. The UVCB is a solid at 20 °C with a molecular weight range between 600 - 1105 g/mol, a water solubility of < 15 µg/L at 20 °C and with particle size 100 – 800 µm. The calculated log Pow value is > 7.97 and the vapour pressure is estimated to be < 0.0001 Pa.

Table 1: Representative constituents of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols with SMILES codes

Constituent

SMILES

Formula

Molecular weight

C16-Alkoxymethyl

COCN(COC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COC

34C30H60N6O6

600.85

C16_C18-Alkoxymethyl

COCN(COCCCCCCCCCCCCCCCCCC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COC

C47H94N6O6

839.3

C16_C18_C18-Alkoxymethyl

COCN(COCCCCCCCCCCCCCCCCCC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COCCCCCCCCCCCCCCCCCC

C64H128N6O6

1077.76

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed (ECHA, 2017).

The water solubility < 15 µg/L and the log Pow value > 7.97 indicate that absorption is likely to occur by micellular solubilisation.In the available acute oral toxicity study according to OECD 423 with Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcoholsno mortality and no adverse clinical signs were observed in any animal. No significant effects on body weight were observed and gross necropsy did not show any treatment-related changes.

Overall, the oral absorption potential of the test substance is expected to be high.

Dermal

A molecular weight less than 100 favours dermal uptake. Above 500 the molecule may be too large. Log Pow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water (ECHA, 2017). With a water solubility < 15 µg/L and alog Pow value > 7.97, dermal absorption rate of the test substance is therefore likely to be low.

There are no data available on dermal absorption of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols. The dermal absorption potential can be calculated from log Pow and molecular weight (MW) applying the following equationdescribed in US EPA (2012):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp was calculated for the representative constituents of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols. The dermal flux rates were estimated to be 0.000399 to1.72 x 109 mg/cm2 per h, indicating low, moderate and high dermal absorption potential for the UVCB substance, respectively (please refer to Table 2, Dermwin v2.02, EpiSuite 4.1).

Table 2: Dermal absorption values for the representative constituents of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols (calculated with Dermwin v 2.02, Epiweb 4.1)

Constituent

SMILES

Dermal flux (mg/cm²/h)

C16-Alkoxymethyl

COCN(COC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COC

0.000399

C16_C18-Alkoxymethyl

COCN(COCCCCCCCCCCCCCCCCCC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COC

30.3

C16_C18_C18-Alkoxymethyl

COCN(COCCCCCCCCCCCCCCCCCC)c1nc(nc(n1)N(COCCCCCCCCCCCCCCCC)COC)N(COC)COCCCCCCCCCCCCCCCCCC

1.72 x 109

 

In the acute dermal toxicity study according to OECD 402, no mortality was observed. The body weight of 4/5 females was reduced during the first week, and reduced in 1/5 females in the second week. During the 14-day observation period 4/5 females showed no body weight gain. This effect was considered to be treatment-related, but as no effects on body weight were seen in the males and no other treatment-related effects were noted, it is not clear whether the lack of body weight gain in some females is toxicologically relevant. A LD50 value of > 2000 mg/kg bw was derived.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). Under conditions of the reconstructed human epidermis test according to OECD 439 and according to OECD 431, no skin irritant and skin corrosive properties were determined, respectively. No local skin irritating effects were observed in the acute dermal toxicity study.

Overall, although the available toxicological data did not confirm a clear systemic bioavailability of the registered substance, a dermal absorption potential of the registered substance cannot be excluded due to the physico-chemical properties and the QSAR calculations.

Inhalation

In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017). Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log Pow >4), particularly those that are poorly soluble in water (1 mg/L or less) (ECHA, 2017).

Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols is a solid with particle sizes between 100 – 800 µm, therefore inhalation cannot be regarded as significant route of exposure. However, if limited absorption occurs following inhalation in the naso-pharyngeal region, the test substancemay be taken up by micellular solubilisation due to the high lipophilicity.

Overall, inhalation potential of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols is considered to be low.

Distribution and accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Lipohilic molecules (log Pow > 0) are favourable for distribution into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty acids (ECHA, 2017).

The molecular weight range between 600 - 1105 g/mol does not favour a high distribution potential.However, due to the lipophilic character (log Pow > 7.97) of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols distribution into cells and the intracellular concentration may be higher than the extracellular concentration particular in fatty tissue. Lipophilic substances will tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate (ECHA, 2017). Overall, since no experimental data are available a bioaccumulation potential cannot be excluded due to the lipophilicity.

Metabolism

No data are available regarding the metabolism of the substance. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox v4.2 (OECD, 2018). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. For the prediction of the metabolism of Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols the representative constituents provided in Table 1 were used. For the constituent C16-Alkoxymethyl, 23 hepatic rat metabolites and 2 dermal metabolites were predicted. Similar results were observed for the constituent C16_C18-Alkoxymethyl, for which 64 metabolites in the liver and 4 metabolites in the skin were predicted. 37 hepatic metabolites and 4 dermal metabolites were predicted for the representative constituent C16_C18_C18-Alkoxymethyl. Most of all these metabolites were hydroxylations of the C16- and C18-alkyl side chains. Based on the results of the OECD QSAR profiling a longer alkyl side chain resulted in multiple hydroxylations and/or oxidation of the hydroxyl groups to aldehydes, ketones or carboxylic acids, therefore more metabolites were predicted for these constituents. These predicted metabolites can be regarded as phase I metabolites, which typically make the substance susceptible to the phase II reactions or conjugation reactions. These transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho(UDP)-glucuronosyltransferases (UGT) and glutathione-S-transferases will generate excretable hydrophilic metabolites by transferring activated glucuronic acid and glutathione to hydroxyl groups of the substrates, respectively (Aktories, 2005). Between 166 and 505 metabolites for the three representative constituents were predicted to result from all kinds of microbiological metabolism. Most of the metabolites were found to be a consequence of the degradation of the molecule in multiple steps.

No indication of a genotoxic reactivity of the test substance was observed in the available genetic toxicity studies on bacteria and mammalian cells in vitro.The available Ames test and the mouse lymphoma assay showed negative results with and without metabolic activation.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa). Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. However, depending on the metabolic changes that may occur, the compound that is finally excreted may have few or none of the physico-chemical characteristics of the parent compound (ECHA, 2017). Theoral absorption potential of the test substance via micellar solubilisation is considered to be high. In addition, based on the OECD QSAR toolbox results described above, Reaction product of 1,3,5-Triazine-2,4,6-triamine, polymer with formaldehyde, methylated and C16-18 fatty alcohols is expected to be hydroxylated within the body and further metabolised inphase II reactions or conjugation reactions to glucuronides or glutathione derivatives. Therefore, the predicted metabolites are expected to mainly be excreted via the faeces.

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005). Allgemeine und spezielle Pharmakologie und Toxikologie.9. Auflage, Urban & Fischer Verlag.

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June, 2017.

OECD (2018). OECD QSAR Toolbox v4.2, Feb 2018, Laboratory of Mathematical Chemistry Oasis. Downloaded from https://qsartoolbox.org/ Prediction performed on 22 May 2018.

US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.1.; Prediction of dermal flux rate: DERMWIN v.2.02 (September 2012); United States Environmental Protection Agency, Washington, DC, USA; Prediction performed on 22 May 2018.