Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

TOXICOKINETIC STATEMENT

In accordance with Annex VIII, Column 1, Item 8.8.1 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is conducted to the extent that can be derived from relevant available information. This comprises a qualitative assessment of the available data on relevant analogue substances as well as substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014) and taking into account further available information.

Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) meets the definition of a UVCB substance, with the main constituents being the potassium salt of oleic acid based sarcosinate (approx. 66% (w/w)) and unreacted oleic acid (approx. 15% (w/w)). Hence the dominant fatty acid moiety present is oleoyl (C18:1). The potassium salts of C16 and C16:1 based sarcosinates are also present in amounts of approx. 5% (w/w) and 2% (w/w), respectively. Water is also contained in substantial amounts (approx. 4% (w/w)). These constitutents therefore attribute to more than 90% of the target substance.

The substance is solid. Its main constituent has a molecular weight of 391.6 g/mol, a low log Pow of 3.1 (QSAR, KOWWIN v1.68) and is highly soluble in water (> 296 g/L at 20 °C (OECD 105, flask method)). The vapour pressure is 0.0026 Pa at 20 °C and 0.11 Pa at 50 °C (OECD 104, dynamic method). The log Pow of the corresponding acid is 6.83 (QSAR, KOWWIN v1.68).

ABSORPTION

Absorption is a function of the potential of 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) and the water solubility. The log Pow provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). Absorption of the target substance in the gastrointestinal tract is in general anticipated because the molecular weight of the main constituent of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is 391.6 g/mol. Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al.; 2001); Ghose et al., 1999) is applied since all rules are fulfilled. With regard to the oral bioavailability it has been shown that after oral ingestion, the analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) was not hydrolysed by either gastric or intestinal enzymes in vitro (CIR, 2001).

There is a study on oral absorption of the analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) which was applied at a dose of 2.6 g per animal to teeth, oral mucosa and tongue of 15 rats and at a volume of 0.3 mL per animal to a group of 3 additional rats. Five rats each were examined at the time of application, and 4 h and 24 h after application; the 3 additional rats were examined 48 h after application. Immediately after administration, the mean distribution of the [14C]Sodium N-lauroylsarcosinate was 1.12% in the teeth, 2.22% in the oral mucosa and 2.95% in the tongue. At 4 h, the mean distribution was 0.92% in the teeth, 0.95% in the oral mucosa, 0.57% in the tongue, 5.44% in the liver, 2.78% in the kidneys, 0.87% in the faeces and 33.5% in the urine. At 24 h the mean distribution was 0.79% in the teeth, 0.92% in the oral mucosa, 0.57% in the tongue, 1.62% in the liver, 0.78% in the kidney, 1.18% in the faeces and 42.2% in the urine. About 1% of the compound adhered to the teeth and the oral mucosa each, and 0.57% adhered to the tongue; this adherence was such that no radioactivity could be washed from those tissues by a physiological saline solution. At 48 h the mean distribution of applied radioactivity was 1.18% in the liver, 13.5% in the bones, 18.7% in the muscles, 2.1% in the faeces and 49.1% in the urine. Only 0.35% of the radioactivity was expired as CO2. The data indicated that sodium N-lauroylsarcosinate was not absorbed by the tissues of the mouth, but was swallowed and absorbed into the blood in the gastrointestinal tract at a rate of more than 80%, distributed into various tissues, not metabolised and rapidly excreted mainly in the urine (Bureau of Biological Research, 1994; CIR, 2001).

Available data on acute and repeated dose toxicity via the oral route of relevant analogue substances are also considered for assessment of the oral absorption potential of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7). An acute oral study conducted with (Z)-N-methyl-N-(1-oxo-9-octadecenyl)glycine (CAS 110-25-8) yielded an LD50 value > 5000 mg/kg bw and no systemic effects at the end of the observation period (Ciba-Geigy, 1981a). Data on repeated dose toxicity is available from a subchronic (90-day) (Huntingdon, 1997) and a 2-year (CIR, 2001) oral study with Sodium N-lauroylsarcosinate (137-16-6). No adverse systemic effects were observed in both studies, and NOAELs of ≥ 250 mg/kg bw/day (highest dose tested) and 1000 mg/kg bw/day (highest dose tested) were derived from the subchronic study and the chronic study, respectively.

The relevant studies of analogue substances indicate that Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) exhibits only a low potential for toxicity after acute and repeated exposure, but no assumptions can be made regarding the absorption potential based on the experimental data. Hence, a systemic bioavailability after oral uptake is considered to be likely.

Dermal

It is commonly accepted that smaller molecules are taken up through the skin more easily than larger ones; the smaller the molecule, the more easily it may be taken up. In general a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large to be absorbed (ECHA, 2014). As the molecular weight of the main constituent of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is 391.6 g/mol, a dermal absorption cannot be excluded. Moreover, if a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. Furthermore, if a substance has been identified as skin sensitiser, then some uptake must have occurred previously, although it may only have been a small fraction of the applied dose (ECHA, 2014).

The available data on skin irritation / skin corrosion of relevant analogue substances are also considered for assessment of the dermal absorption potential of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl) aminoacetate (CAS 76622-74-7). In reliable in vivo studies, Sodium N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 3624-77-9) and N-(1-oxooctadecyl)sarcosine (CAS 142-48-3) met the criteria for classification as irritating to the skin according to Regulation (EC) No. 1272/2008. However, no further local or systemic effects were observed. Moreover, in another reliable in vivo study (Z)-N-methyl-N-(1-oxo-9-octadecenyl)glycine (CAS 110-25-8) also met the classification criteria for skin irritation. As opposed to the first two studies, in the latter study absence of hair on the whole application area was apparent in all animals. In consequence, an enhanced penetration of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) due to local skin damage cannot be excluded.

However, no skin sensitisation potential has been identified for the analogue substances Sodium N-lauroylsarcosinate (CAS 137-16-6), Glycine, N-methyl-, N-coco acyl derivatives, sodium salts (CAS 61791-59-1) and (Z)-N-methyl-N-(1-oxo-9-octadecenyl)glycine (CAS 110-25-8) and hence no sensitisation potential is anticipated for Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7).

In general, the dermal uptake of substances with a water solubility of > 10 g/L (and log Pow < 0) will be low, as those substances may be too hydrophilic to cross the stratum corneum. Log Pow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), in particular if water solubility is high. In contrast, log Pow values below -1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low (ECHA, 2014). As the main constituent of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) has a log Pow of 3.1 (the log Pow of the corresponding acid is 6.83) and is highly water soluble, dermal uptake cannot be excluded.

The available data on dermal toxicity of the relevant analogue substances N-lauroylsarcosine (CAS 97-78-9), Sodium N-methyl-N-(1-oxotetradecyl)aminoacetate (CAS 30364-51-3) and Ammonium N-methyl-N-(1-oxododecyl)glycinate (CAS 68003-46-3) are also considered for assessment of the dermal absorption potential of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7). At the limit concentration of 2000 mg/kg bw in rats no mortality occurred and no signs of systemic toxicity were observed in all studies available (Phycher, 2014; Harlan, 2013; Frey-Tox, 2016). An alternative possible explanation for the lack of systemic toxicity via the dermal route, apart from a low toxicological potential, could be limited dermal absorption. However, based on the available data the reason for the lack of acute toxicity via the dermal route cannot be unequivocally decided.

Considering all available data on relevant analogue substances as well as the relevant physical-chemical properties of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7), a low dermal absorption is assumed.

Inhalation

Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) has a vapor pressure of 0.0026 Pa at 20 °C and 0.11 Pa at 50 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and therefore availability for respiratory absorption in the form of vapors or gases, is not expected to be significant.

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. Moreover, log Pow values in the range -1 to 4 are favorable for absorption directly across the respiratory tract epithelium by passive diffusion, while lipophilic compounds with a log Kow > 4, that are poorly soluble in water (1 mg/L or less), can be taken up by micellar solubilisation (ECHA, 2014).

Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is a white solid or pasty scales at 20 °C and is marketed only in solid or granular form. Therefore, the probability of inhalative exposure is deemed to be rather low.

The available data on the acute inhalation toxicity of the analogue substance (Z)-N-methyl-N-(1-oxo-9-octadecenyl)glycine (CAS 110-25-8) are also considered for assessment of the inhalative absorption potential of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7). The substance was tested as liquid aerosol (mist) and the LC50 for males and females was determined to be 1.05 mg/L air and 1.8 mg/L air, respectively (BASF, 1979). Therefore, the substance is classified for acute inhalation toxicity, category 4, according to Regulation (EC) No. 1272/2008. Mortalities occurred and clinical signs observed included flight attempts, gasping and noisy breathing, bloody nose area, low motility, hair loss, salivation, and abusive pain reflex.

Overall, taking the physico-chemical parameters and the acute inhalation toxicity data into consideration, respiratory absorption of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is assumed to be possible, but rather low.

DISTRIBURTION / ACCUMULATION

Since no data on the distribution and accumulation of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) are available, the oral absorption study mentioned above performed with the analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) is used to derive information. The distribution of [14C]Sodium N-lauroylsarcosinate (137-16-6) was investigated by applying the substance to teeth, oral mucosa and tongue of 15 rats at a dose of 2.6 g per animal. The distribution of the radioactivity in tissues at the time of treatment was 0.09 mg/g in the teeth, 0.1 mg/g in the oral mucosa, and 0.1 mg/g in the tongue. Four hours after treatment the distribution was 0.07 mg/g in the teeth, 0.05 mg/g in the oral mucosa, 0.02 mg/g in the tongue, 0.003 mg/g in the blood, 0.015 mg/g in the liver, 0.026 mg/g in the kidneys, 0.006 mg/g in the bones and 0.009 mg/g in the muscles. At 24 hours the distribution was 0.09 mg/g in the teeth, 0.05 mg/g in the oral mucosa, 0.02 mg/g in the tongue, 0.003 mg/g in the blood, 0.005 mg/g in the liver, 0.008 mg/g in the kidneys, 0.01 mg/g in the bones and 0.006 mg/g in the muscles (Bureau of Biological Research, 1994; CIR, 2001).

In other studies by the same investigators the teeth of rats were brushed with dentifrice containing 2 x 10³ µg [14C]Sodium N-lauroylsarcosinate. The test substance was taken up from the dentifrice by the teeth, oral mucosa and tongue in a way that a certain amount could not be rinsed away with saline solution. However, frequent application did not cause accumulation of radioactivity in bone or muscle above the one mentioned earlier in this assessment (Bureau of Biological Research, 1994; CIR, 2001).

METABOLISM / EXCRETION

Again, no data about metabolism or excretion of Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) are available and therefore the oral absorption study already mentioned performed with the analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) is used to derive information. In this study, [14C]Sodium N-lauroylsarcosinate (CAS 137-16-6) was applied to teeth, oral mucosa, and tongue of 15 rats at a dose of 2.6 g per animal and at a volume of 0.3 mL per animal to a group of 3 additional rats. Approximately 34% of the activity of the test material was excreted in the urine over a period of 4 h after application, demonstrating rapid absorption and excretion. Some 42% of the activity were excreted during 24 h, and approximately 49% were excreted during 48 h. The remainder of the activity could approximately be accounted for by estimating the total amount of activity in the blood, muscles, bone and other tissues of the body, indicating that very little, if any, of the compound was oxidized to form CO2 (Bureau of Biological Research, 1994; CIR, 2001).

In addition, further experimental data show that after oral administration of [14C]Sodium N-lauroylsarcosinate (CAS 137-16-6) to rats 82 to 89% of a 50 mg/kg bw dose was excreted in the urine and faeces within 24 h. For the next 24 h, 1 to 2% was excreted. Nearly all of the excreted material was found in the urine (CIR, 2001).

Finally, the fact that the predominant function of a group of substances structurally similar to Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7), the N-acyl amino acids, is the detoxification and excretion of xenobiotic carboxylates (Farrel, 2008) strengthens the hypothesis that the main excretion route for Potassium (Z)-N-methyl-N-(1-oxo-9-octadecenyl)aminoacetate (CAS 76622-74-7) is by urinary excretion.