Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Dermal absorption:

Permeation 10.3% after 12 h and 46.5% after 24 h (hairless mouse skin in vitro)

Permeation 0.4% after 30 min (human skin in vivo)

Key value for chemical safety assessment

Additional information

In accordance with Article 13 (1) of Regulation (EC) No. 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular, information shall be generated whenever possible by means other than vertebrate animal tests, through the use of alternative methods, for example, in vitro methods or qualitative or quantitative structure-activity relationship models or from information from structurally related substances (grouping or read-across).” According to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006, substances may be considered as a group provided that their physicochemical, toxicological and ecotoxicological and environmental fate properties are likely to be similar or follow a regular pattern as a result of structural similarity. The substances within the analogue approach (listed inTable1) are considered to apply to these general rules and the similarity is justified on basis of scope of variability and overlapping of composition, representative molecular structure, physico-chemical properties, ecotoxicological profiles and supported by various (Q)SAR methods. There is convincing evidence that these chemicals lie in the overall common profile of this analogue approach. The key points that the target and source substances share are:

(i)           Common functional groups:The substances included in the analogue approach are alkyl betaines (dimethyl or amidopropyl dimethyl). They are amphoteric surfactants demonstrating zwitterionic character. The aliphatic chain length is predominantly C12 to C14.

(ii)          Similar physico-chemical properties:All betaines within the analogue approach are solid. They decompose while heated above 100 °C and they are non-volatile. The octanol/water partition coefficients (log Pow) are low, slightly increasing with the fatty acid chain length, but not exceeding the value of 3. The substances are well soluble in water, they are surface active and they demonstrate dissociating properties.

(iii)         Common properties for environmental fate & eco-toxicological profile:The substances are readily biodegradable, have no significant potential for bioaccumulation and have a low adsorption potential. Furthermore, the available data indicate the same ecotoxicologigal profile; all available data are in the same order of magnitude.


Metabolic pathways

Toxicokinetic, metabolism and distribution

No toxicokinetic studies are available for Betaines, C12-14 (even numbered)-alkyldimethyl, but testing is not required under REACH.

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of Betaines, C12-14 (even numbered)-alkyldimethyl was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

Two studies focusing on dermal absorption, which will be the main route of exposure considering the uses of betaines, in mice and humans are available for CAS No. 683-10-3 which were used for read-across following the analogue approach (Ridout et al., 1991; Buck et al., 1993).


Betaines, C12-14 (even numbered)-alkyldimethyl (average molecular weight of ca. 279 g/mol) is a white solid, which is soluble in water (324 g/L at room temperature). It has a log Pow of -0.4 at 20 °C and a vapour pressure of 1E-07 Pa at 25 °C.


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, 2012).


Oral:

The smaller the molecule, the more easily it may be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). Since the average molecular weight of Betaines, C12-14 (even numbered)-alkyldimethyl is ca. 279 g/mol, absorption of the molecule in the gastrointestinal tract is in general anticipated.

Moreover, absorption after oral ingestion of Betaines, C12-14 (even numbered)-alkyldimethyl is also expected when the “Lipinski Rule of Five” (Lipinski et al., 2001; Ghose et al., 1999) is applied, as all rules are fulfilled.

As the substance is soluble in water, it will dissolve in gastrointestinal fluids. However, the log Pow of -0.4 suggests absorption of the substance via passive diffusion.

Additionally, there are reliable experimental data available investigating the acute oral toxicity of the structural analogue substance CAS No. 68424-94-2 (Levenstein, 1979), and there is a study even for Betaines, C12-14 (even numbered)-alkyldimethyl itself (Huntingdon Research Centre, 1969). Both studies demonstrated LD50 values of the same order of magnitude (2640 mg/kg bw in mice and 3202 mg/kg bw in rats, respectively). Mortality was observed in both studies. For Betaines, C12-14 (even numbered)-alkyldimethyl necropsy of the deceased animals revealed gastrointestinal inflammation. Such effects were not noticed at necropsy of the surviving animals. Therefore, the mortality observed in this study had to be attributed to local irritant effects of the test substance rather than systemic toxicity. No necropsy results were reported in the study with the structural analogue; therefore, local inflammation as reason for mortality cannot unequivocally be excluded, but absorption via the gastrointestinal tract and subsequent systemic toxicity cannot be excluded, either.

Based on these results, no unequivocal conclusions on the oral absorption potential of the substance are possible. 

In summary, according to its physico-chemical properties, absorption of Betaines, C12-14 (even numbered)-alkyldimethyl is possible and has to be anticipated. However, as the substance is classified as corrosive according to Regulation (EC) No 1272/2008 and EU Directive 67/548/EEC, the local effects will probably be more predominant than the systemic toxicity.


Dermal:

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption; above 500 the molecule may be too large. Log Pow values between 1 and 4 favour dermal absorption particularly if water solubility is high. For substances with log Pow values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption, whereas a water solubility between 100 – 10000 mg/L suggests absorption to be moderate to high (ECHA, 2012). As Betaines, C12-14 (even numbered)-alkyldimethyl has an average molecular weight of ca. 279 g/mol and a log Pow of -0.4 paired with a high water solubility, dermal absorption is likely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As the neat substance is considered as corrosive in humans, an enhanced penetration of the substance due to local skin damage cannot be excluded.

Additionally, QSAR prediction for the skin absorption potential of Betaines, C12-14 (even numbered)-alkyldimethyl resulted in a medium high dermal absorption potential of about 40% (Mostert, V. and Goergens, A., 2011).

Furthermore, there is one publication on permeation through and sequestration in mouse skin in vitro available for CAS No. 683-10-3 which is used as read-across source substance (Ridout et al., 1991). In this study a 16 mM dilution of radioactively labelled C12BET was applied to full thickness skin samples isolated from hairless mice, and permeation was measured after 12 and 24 hours.

While 46.5% had penetrated the skin after 24 hours (10.3% after 12 hours), approximately 25% of the applied dose was sequestrated within the skin. Total recovery of radioactivity was nearly 75% of the applied dose, indicating a high dermal absorption potential of the test substance.As dermal absorption cannot be extrapolated for time because too many factors like applied dose (amount of applied substance per area), saturation of the skin with substance (further increase of concentration/amount will not enhance penetration), polarity and molecular weight of the substance play a role, absorption of 10% is adopted for the duration of an 8h shift and used for chemical safety assessment.

Additionally, the influence on skin barrier function for other substances after pre-treatment with C12BET was addressed. Pre-treatment with C12BET at all concentrations significantly (p<0.05) promoted penetration of the indicator substance nicotinamide across hairless mouse skin when compared with the controls.


Published data of an in vivo dermal penetration study in human volunteers with the same substance demonstrated a maximum uptake of only 0.4% of the applied dose, which was primarily localized in the outer layers of the stratum corneum (Bucks et al., 1993). However, the investigation of the dermal absorption was conducted only 30 minutes after application of the test substance. Systemic availability of the applied test substance was not tested.

Acute dermal toxicity of the analogue substance CAS No. 61789-40-0 was investigated in male and female rats (Kao, 1987). No systemic toxicity was observed up to the highest dose tested (LD50 > 620 mg/kg bw a.i.). However, local irritation of the treated skin sites was noticed in all animals. Based on this study no decision can be made if the lack of systemic effects is due to a low toxicity of the substance or a lack of absorption via the skin.

In summary, based on all available data, a dermal absorption of Betaines, C12-14 (even numbered)-alkyldimethyl is likely.


Inhalation:

Betaines, C12-14 (even numbered)-alkyldimethyl is of low volatility: calculated vapour pressure is 1E-07 Pa at 25 °C. However, if the substance is sprayed, it may be available for respiratory absorption after inhalation of aerosols. 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 15 µm the alveolar region of the respiratory tract (ECHA, 2012).

The substance is marketed in a non-solid form only (aqueous formulations) and has a very low vapour pressure; therefore exposure to dusts or vapours can be excluded. If used in spray applications the content of active ingredient will not exceed a maximum of 15% in products available for the general population, and due to the irritant nature of the substance corresponding RMMs are established in the industrial and professional sectors; therefore, exposure to and subsequent absorption of relevant amounts via inhalation is unlikely.


Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Distribution of Betaines, C12-14 (even numbered)-alkyldimethyl within the body cannot be excluded. Due to the fact that the test substance has an average molecular weight of ca. 279 g/mol, a water solubility of 324 g/L and a log Pow of -0.4 it is assumed that it will be mainly distributed in aqueous compartments of the body. With a log Pow < 0 and a water solubility of 324 g/L, an accumulation of the substance in the fatty tissue is rather unlikely.


Metabolism

Based on the chemical structure of Betaines, C12-14 (even numbered)-alkyldimethyl, metabolism into chemically reactive compounds under in vivo conditions is unlikely. However, no experimental data on metabolism of alykldimethyl betaines is available. For the cocamidopropy betaines excretion of the largest part of the applied doses as unchanged parent material in the faeces was demonstrated, minor parts were excreted in the urine and in exhaled air (5 and 1%, respectively) (HERA, 2005). Therefore, anticipation of a comparable metabolical fate of alkyl dimethyl betaines is justified.


Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine.

In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar, and have a high molecular weight. In general, for organic cations with a molecular weight below 300 it is unlikely that more than 5-10% will be excreted in the bile. For organic anions this cut off value may be lower. Substances excreted via bile may potentially undergo enterohepatic circulation (ECHA, 2012).

As Betaines, C12-14 (even numbered)-alkyldimethyl has an average molecular weight of ca. 279 g/mol and contains polar and non-polar regions it is assumed that one part of the substance burden will be excreted via the bile and faeces. However, as the substance is well soluble in water (324 g/L), the fraction of the substance burden which is not excreted via the faeces will be excreted via urine. This assumption is in accordance with the observations made for cocamidopropyl betaines (HERA, 2005).