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Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Control animals:
no
Type:
distribution
Results:
1.12% teeth, 2.22% oral mucosa and 2.95% tongue; immediately after application
Type:
distribution
Results:
0.92% teeth, 0.95% oral mucosa, 0.57% tongue, 5.44% liver and 2.78% kidney; 4 h after application
Type:
distribution
Results:
0.79% teeth, 0.92% oral mucosa, 0.57% tongue, 1.62% liver, 0.78% kidney; 24 h after application
Type:
excretion
Results:
0.87% faeces and 33.5% urine; 4 h after application
Type:
excretion
Results:
1.18% faeces and 42.2% urine; 24 h after application
Type:
metabolism
Results:
0.35% were expired as CO2; 48 h after application
Type:
distribution
Results:
1.18% liver, 13.5% bones and 18.7% muscles; 48 h after application
Type:
excretion
Results:
2.1% feces and 49.1% urine; 48 h after application
Details on absorption:
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 was excreted during 24 h. The remainder of the activity could be accounted for approximately by estimating the total amount of activity in the blood, muscles, bone and other tissues of the body, such an estimate indicating that very little, if any, of the compound was oxidized to form CO2.
Details on distribution in tissues:
See Table 1 under "Any other information on results incl. tables".
Details on excretion:
The data demonstrated the rapid excretion of 14C from the body and suggested that little of the compound is metabolized and/or held within the tissues.

Table 1. Distribution of 14C (% of the activity administered) 48 h after application.

Organ

Average of 3 rats (%)

Liver

1.18

Bone

13.5

Muscle

18.7

Feces

2.1

Urine

49.1

CO2 expired

0.35

Description of key information

Absorption

A systemic bioavailability after oral uptake of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7) is considered likely. Based on physico-chemical properties, dermal and inhalation uptake is likely to be low.

Distribution/Accumulation

Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7) is not distributed to a significant degree in the body. No bio-accumulation potential has been identified.

Metabolism/Excretion

No metabolism is anticipated for reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7). Approx. 82 - 89% of the substance are excreted within 24 h after oral application. The main excretion pathway is via urine.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic, metabolism and distribution

In accordance with Annex VIII, Column 1, Item 8.8.1 of Regulation (EC) No. 1907/2006 (REACH) 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 mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine 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 Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information from adequate analogue substances.

Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine meets the definition of a multi-constituent substance based on the analytical evaluation. Its constituents are stearoyl sarcosine (40 - 65%) and palmitoyl sarcosine (25 - 50%). Myristoyl sarcosine (0 - 3%) and lauroyl sarcosine (0 - 2%), i.e. sarcosines with a shorter alkyl chain, are present in small amounts. Moreover, the unreacted fatty acids stearic acid and palmitic acid have been identified in amounts of < 10% and 0 - 5%, respectively. Since all impurities identified are not expected to exhibit a toxicological profile that differs significantly from that of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine, no impact on the toxicological and toxicokinetic assessment is expected. The constituents of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine have molecular weights of 327.51 g/mol (palmitoyl sarcosine) and (stearoyl sarcosine) 355.56 g/mol. The log Pow and the water solubility were determined to be 5.7 (OECD 117, HPLC method) and 2.86 mg/L, respectively. The measured vapour pressure is 7.1 x 10E-5 Pa at 20 °C (OECD 104, effusion method).

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) 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

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2017). As the molecular weights of the constituents of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine are 327.51 and 355.56 g/mol, absorption of the molecules in the gastrointestinal tract is in general anticipated. Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al.; 2001); Ghose et al., 1999) is applied to reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine since all rules are almost fulfilled. The log Pow of 5.7 is considered to be close enough to the limit of 5 as defined in the “Lipinski Rule of Five”. Furthermore, with regard to the oral bioavailability it has been shown that after oral ingestion, the analogue substance sodium N-lauroylsarcosinate (CAS No. 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 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 (CIR, 2001). Five rats each were examined at the time of application, and 4 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 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 reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine. An acute oral study conducted with N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC No. 701-177-3) yielded an LD50 value > 5000 mg/kg bw and no systemic effects at the end of the observation period. Data on repeated dose toxicity is available from a subchronic (90-day) and a 2-year oral study with sodium N-lauroylsarcosinate. 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.

Thus, the available studies from analogue substances indicate only a low potential for toxicity after acute and repeated exposure following oral exposure. No obvious assumptions can be made regarding the absorption potential based on the experimental data. Nevertheless, when theoretical considerations and experimental data are accounted for, a systemic bioavailability after oral uptake of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine is considered likely.

Dermal

It is commonly accepted that smaller molecules are taken up through the skin more easily than bigger 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, 2017). As the molecular weights of the constituents of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine are 327.51 and 355.56 g/mol, a dermal absorption of the molecules cannot be excluded.

In general, the dermal uptake of substances with a high 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 < -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, 2017). As glycine, N-methyl, N-coco acyl derivs, sodium salt has a log Pow value of 5.7 and is slightly water soluble, dermal uptake is likely to be low.

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 sensitizer, then some uptake must have occurred previously, although it may only have been a small fraction of the applied dose (ECHA, 2017). The available data on skin irritation/ corrosion of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine are also considered for assessment of dermal absorption. In an in vivo irritation study, reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine was demonstrated to be irritating to skin. Therefore, an enhanced penetration of the neat substance due to local skin damage may not be excluded. Furthermore, no skin sensitisation potential has been identified for reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine based on in vitro and in vivo investigations with adequate analogue substances.

Based on theoretical considerations and experimental data, reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine is considered to have only a low potential for dermal absorption.

Inhalation

Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine has a vapor pressure of 7.1 x 10E-5 Pa at 20 °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 (ECHA, 2017). Moreover, moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine is marketed in aqueous formulations. Due to the anticipated use pattern of the substance, spray applications are not expected. Hence, generation of inhalable material cannot occur under normal and reasonably foreseeable conditions of use.

The available data on the acute inhalation toxicity of the analogue substance N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC No. 701-177-3) are also considered for assessment of the inhalative absorption potential of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine. 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. An overall LC50 value for male and female rats of 1.37 mg/L air has been stated by the authors. Therefore, the substance is classified for acute inhalation toxicity (Acute Tox. 4, H332) according to Regulation (EC) No. 1272/2008 (CLP). 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. However, it is more likely that the effects observed originate from severe local irritation in the respiratory tract rather than from a systemic toxicity.

Overall, considering the physico-chemical parameters and the anticipated uses of the substance as well as the form in which it is placed on the market, respiratory absorption of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine is assumed to be possible, but rather low.

Distribution/Accumulation

Since no data on the distribution and accumulation of reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine are available, the oral absorption study mentioned above performed with the analogue substance sodium N-lauroylsarcosinate is used to derive information. [14C]Sodium N-lauroylsarcosinate was applied 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 reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine are available and therefore the oral absorption study already mentioned performed with the analogue substance sodium N-lauroylsarcosinate is used to derive information. In this study [14C]sodium N-lauroylsarcosinate 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 was 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 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 major function of a group of substances structurally similar to sarcosines and sarcosinates, the N-acyl amino acids, would appear to be in the detoxification and excretion of xenobiotic carboxylates (Farrel, 2008) strengthens the hypothesis that the main excretion route for reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine is by urinary excretion.

References

Bureau of Biological Research (1994). The distribution of C14 from compound 105 in the rat. Hampshire Chemical Corporation. 3: 58-66.

CIR (2001). Final Report on the Safety Assessment of Cocoyl Sarcosine, Lauroyl Sarcosine, Myristoyl Sarcosine, Oleoyl Sarcosine, Stearoyl Sarcosine, Sodium Cocoyl Sarcosinate, Sodium Lauroyl Sarcosinate, Sodium Myristoyl Sarcosinate, Ammonium Cocoyl Sarcosinate, and Ammonium Lauroyl Sarcosinate” (see IJT, 10 (Suppl1): 1-14, 2001)

Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

ECHA (2017). Guidance on information requirements and chemical safety assessment - Chapter 7c: Endpoint specific guidance; Version 3; June 2017; European Chemicals Agency, Helsinki, Finland

Farrel EK and Markler DJ (2008). Biosynthesis, degradation and pharmacological importance of the fatty acid amides. Drug Discovery Today 13 (13-14): 558-568

Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.