Ammonium N-methyl-N-(1-oxododecyl)glycinate

Endpoint summary

Link to relevant study record(s)

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 report provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Type:

distribution

Results:

1.12% teeth, 2.22% oral mucosa and 2.95% tongue; immediately after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

distribution

Results:

0.92% teeth, 0.95% oral mucosa, 0.57% tongue, 5.44% liver and 2.78% kidney; 4 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

distribution

Results:

0.79% teeth, 0.92% oral mucosa, 0.57% tongue, 1.62% liver, 0.78% kidney; 24 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

excretion

Results:

0.87% faeces and 33.5% urine; 4 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

excretion

Results:

1.18% faeces and 42.2% urine; 24 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

metabolism

Results:

0.35% were expired as CO2; 48 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

distribution

Results:

1.18% liver, 13.5% bones and 18.7% muscles; 48 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

Type:

excretion

Results:

2.1% feces and 49.1% urine; 48 h after application. Source: CAS 137-16-6, Bureau of Biological Research, 1994

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.
Source: CAS 137-16-6, Bureau of Biological Research, 1994

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.
Source: CAS 137-16-6, Bureau of Biological Research, 1994

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

Source: CAS 137-16-6, Bureau of Biological Research, 1994

Description of key information

Absorption

A systemic bioavailability after oral uptake of ammonium N-methyl-N-(1-oxododecyl)glycinate is considered likely. Based on physico-chemical properties, dermal and inhalation uptake is likely to be low.

Distribution/Accumulation

Ammonium N-methyl-N-(1-oxododecyl)glycinate is not distributed to a significant degree in the body. No bio-accumulation potential has been identified.

Metabolism/Excretion

No metabolism is anticipated for ammonium N-methyl-N-(1-oxododecyl)glycinate. 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 ammonium N-methyl-N-(1-oxododecyl)glycinate (CAS No. 68003-46-3) 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.

Ammonium N-methyl-N-(1-oxododecyl)glycinate meets the definition of a mono-constituent substance based on the analytical evaluation. Ammonium laurate is present as an impurity in small amounts. As neither ammonium cations nor laurate anions are of toxicological relevance, no impact on the toxicological characterisation of ammonium N-methyl-N-(1-oxododecyl)glycinate is expected as a result of the impurity. It is important to note that ammonium N-methyl-N-(1-oxododecyl)glycinate is not manufactured as neat substance. Its production takes place in situ in an aqueous environment and the resulting technical product contains about 30% of the main constituent ammonium N-methyl-N-(1-oxododecyl)glycinate and approx. 70% water. Since the substance changes its chemical nature if the water is removed, water is considered an additive to ensure the structural integrity of the registered substance.

The molecular weight of neat ammonium N-methyl-N-(1-oxododecyl)glycinate is 288.43 g/mol and the log Pow has been estimated (QSAR, EPISuite v 4.10, KOWWIN v1.68) based on the log Pow values for lauroyl sarcosinate and for lauric acid. While the first is 4.1, the latter is calculated to be 5.0 and hence the log Pow value of ammonium N-methyl-N-(1-oxododecyl)glycinate is expected to be of the same order of magnitude. The vapour pressure was experimentally determined to be 2604 Pa @ 20 °C (OECD 104; LAUS, 2016). However, as water is contained to about 70% in the substance because it is necessary to stabilise the main constituent ammonium N-methyl-N-(1-oxododecyl)glycinate, the value determined reflects to a large extend the vapour pressure of water (2340 Pa @ 20 °C; Weast, 1983) rather than that of the main constituent ammonium N-methyl-N-(1-oxododecyl)glycinate. Therefore, the vapour pressure of the main constituent was calculated and the theoretical value of 5.1 x 10E-5 Pa @ 25 °C (QSAR, EPI Suite v4.11, MPBVP v1.43) is considered more relevant in terms of toxicological effects and is, therefore, used in the assessment of the toxicokinetic behaviour.

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 weight of ammonium N-methyl-N-(1-oxododecyl)glycinate is 288.43 g/mol, absorption of the molecule 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 ammonium N-methyl-N-(1-oxododecyl)glycinate since all rules are fulfilled. 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).

Data on acute oral toxicity of ammonium N-methyl-N-(1-oxododecyl)glycinate are available whereas its repeated dose toxicity has not been investigated. Therefore, the available data on repeated dose toxicity via the oral route of an adequate analogue substance are also considered. Ammonium N-methyl-N-(1-oxododecyl)glycinate was tested for acute toxicity by gavage in rats of both sexes; the dose level was set at 2000 mg/kg bw. All animals showed a hunched posture and piloerection starting 30 min after dosing. From Day 1 to the end of the observation period on Day 14 the animals were free of any abnormalities. No mortalities and no further effects of toxicological relevance have been observed and hence the LD50 value was determined to be > 2000 mg/kg bw. Data on repeated dose toxicity are available from a subchronic and a 2-year (chronic) 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 on ammonium N-methyl-N-(1-oxododecyl)glycinate and the analogue substance sodium N-lauroylsarcosinate reveal only a low potential for toxicity after acute and repeated exposure. Thus, no obvious assumptions can be made regarding the absorption potential based on the experimental data. Nevertheless, a systemic bioavailability after oral uptake of ammonium N-methyl-N-(1-oxododecyl)glycinate 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 main constituents of ammonium N-methyl-N-(1-oxododecyl)glycinate is 288.43 g/mol, a dermal absorption of the molecules cannot be excluded.

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 ammonium N-methyl-N-(1-oxododecyl)glycinate are also considered for assessment of dermal absorption. In an in vivo irritation study, the registered substance was demonstrated to be not irritating to skin. Therefore, an enhanced penetration of ammonium N-methyl-N-(1-oxododecyl)glycinate due to local skin damage may be excluded. Furthermore, no skin sensitisation potential has been identified in in vitro and in vivo studies performed with analogue source substances glycine, N-methyl-, N-coco acyl derivatives, sodium salts (CAS 61791-59-1), N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC 701-177-3), sodium N-lauroylsarcosinate (CAS 137-16-6), and sodium N-methyl-N-(1-oxotetradecyl)aminoacetate (CAS 30364-51-3). Thus, also for ammonium N-methyl-N-(1-oxododecyl)glycinate no sensitisation potential and an enhanced skin penetration is expected.

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 ammonium N-methyl-N-(1-oxododecyl)glycinate has a log Pow value in the range of 4.1 – 5.0 and has a good solubility in water (it is produced in an aqueous environment containing about 30% of its main constituent ammonium N-methyl-N-(1-oxododecyl)glycinate and 70% water which is needed to stabilise the main constituent), dermal uptake is likely to be low.

Overall, accounting for all theoretical considerations and in view of the absence of any experimental evidence clearly supporting the assumption of high dermal absorption, ammonium N-methyl-N-(1-oxododecyl)glycinate is considered to have only a low potential for dermal absorption.

Inhalation

As mentioned earlier, ammonium N-methyl-N-(1-oxododecyl)glycinate is manufactured and marketed containing approx. 70% water which is needed as additive to stabilize the main constituent ammonium N-methyl-N-(1-oxododecyl)glycinate. Hence, experimental determination of its vapour pressure is rather challenging. Therefore, the vapour pressure of the main constituent has been estimated using a commonly accepted QSAR methodology (EPI Suite v4.11, MPBVP v1.43) to be 5.1 x 10E-5 Pa @ 25 °C. Based on the low vapour pressure value, vapours of ammonium N-methyl-N-(1-oxododecyl)glycinate are unlikely to be available for respiratory absorption in the lung. 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. In addition, due to the anticipated use pattern of the substance, no spray applications are expected. Hence, generation of inhalable material cannot occur under normal and reasonably foreseeable conditions of use.

Overall, considering the physico-chemical parameters and the anticipated uses of the substance, respiratory absorption of ammonium N-methyl-N-(1-oxododecyl)glycinate is assumed to be possible, but rather low.

Distribution / Accumulation

Since no data on the distribution and accumulation of ammonium N-methyl-N-(1-oxododecyl)glycinate are available, the oral absorption study mentioned above performed with the analogue substance sodium N-lauroylsarcosinate is used to derive information. The distribution of [14C]sodium N-lauroylsarcosinate 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 ammonium N-methyl-N-(1-oxododecyl)glycinate 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 ammonium N-methyl-N-(1-oxododecyl)glycinate 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

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

LAUS (2016). Determination of the vapour pressure of Perlastan AL-30 according to OECD 104 resp. EU A.4 using the static method; Testing facility: LAUS GmbH, Auf der Schafweide 20, D-67489

Kirrweiler, Germany; Report no. 15121103G946; Study sponsor: Schill + Seilacher GmbH; Report date: 2016-11-30

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.

Weast (1983). Handbook of Chemistry and Physics, 64th Edition, 1983-1984, CRC Press Inc., Boca Raton, Florida