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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Objective of study:
absorption
distribution
excretion
Principles of method if other than guideline:
Determination of the tendency of the test substance to adhere to the teeth and oral mucosa and the exrection and distribution of 14C from the compound swallowed and absorbed into the rat. Furthermore, the metabolism of the test material to yield radioactive CO2 was observed.
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
other: applied with a micro-pipette to teeth, oral mucosa and tongue
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was dissolved in water to form a solution having 3.36E6 counts per minute per mL of solution.
Duration and frequency of treatment / exposure:
single treatment
Dose / conc.:
2.58 other: mg/rat
Remarks:
Experiment A (distribution)
Dose / conc.:
0.3 other: mL/rat
Remarks:
Experiment B (metabolism)
No. of animals per sex per dose:
5 animals at 0, 4 and 24 h after application (distribution)
3 animals (metabolism)
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, teeth, oral mucosa, tongue, liver, kidney and bone muscle.
- Time and frequency of sampling: at 0, 4 and 24 h after application

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces and expired CO2
- Time and frequency of sampling: 48 h
- From how many animals: 3
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

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 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 N-methyl-N-(C18-(unsaturated)alkanoyl)glycine 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 on N-methyl-N-(C18-(unsaturated)alkanoyl)glycine.

N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is a liquid. It meets the definition of a UVCB substance and its main constituent has a molecular weight of 353.54 g/mol. The water solubility and the vapour pressure of the UVCB substance have been determined to be 0.44 mg/L (21 °C; EU A.6, column elution) and 1.31E-4 Pa (20 °C; EU A.4, effusion method), respectively. The log Pow was established to be in the range ≥ 3.5 to ≤ 4.2 (20 °C; EU A.8, HPLC method), reflecting its complex composition.

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 the main consitutent of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is 353.54 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 since all rules are fulfilled. With regard to the oral bioavailability it has been shown that after oral ingestion, the structural analogue substance Sodium lauroyl sarcosinate was not hydrolysed by either gastric or intestinal enzymes in vitro (CIR, 2001).

As no toxicokinetic data of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine are available, information obtained with the structural analogue substance Sodium N-lauroylsarcosinate are assessed. There is a study on oral absorption of 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. 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 lauroyl sarcosinate 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 lauroyl sarcosinate 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).

The available data on acute and repeated dose toxicity via the oral route of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine are also considered for assessment of oral absorption. An acute oral toxicity study conducted with N-methyl-N-(C18-(unsaturated)alkanoyl)glycine showed an LD50 value > 5000 mg/kg bw (Ciba Geigy, 1980). Clinical signs observed include dyspnoea, slight exophthalmos, slight to moderate ruffled fur and slight to moderate diarrhoea as well as a slightly curved body position. All animals recovered within 7 days. The clinical signs, however, are attributed to the irritating properties of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine rather than to a systemic toxicity. This finding is further supported by another oral acute toxicity study performed with N-methyl-N-(C18-(unsaturated)alkanoyl)glycine, resulting in an LD50 value of 9200 mg/kg bw (BASF, 1979a).

Data on repeated dose toxicity are available from a subchronic and a 2-year oral study with the analogue substance Sodium N-lauroylsarcosinate (Huntingdon, 1997; CIR, 2001). 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.

Available studies show that N-methyl-N-(C18-(unsaturated)alkanoyl)glycine has 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. Overall, a systemic bioavailability after oral uptake of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine 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 weight of the main consitutent N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is 353.54 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 N-methyl-N-(C18-(unsaturated)alkanoyl)glycine are also considered for assessment of dermal absorption. Three irritation/corrosion studies are available for N-methyl-N-(C18-(unsaturated)alkanoyl)glycine. In an in vitro skin corrosion study the test item was demonstrated to be non-corrosive (Frey-Tox, 2005). In two in vivo irritation studies conducted with the neat substance, N-methyl-N-(C18-(unsaturated)alkanoyl)glycine was demonstrated to be irritating to skin (Hazleton, 1991; Ciba Geigy, 1981). Therefore, an enhanced penetration of the neat substance due to local skin damage cannot be excluded. Furthermore, no skin sensitisation potential has been identified for N-methyl-N-(C18-(unsaturated)alkanoyl)glycine.

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 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, 2017). As N-methyl-N-(C18-(unsaturated)alkanoyl)glycine has a log Pow in the range ≥ 3.5 to ≤ 4.2 and a water solubility of 0.44 mg/L dermal uptake is likely to be low but cannot be excluded entirely.

Overall, N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is considered to have only a low potential for dermal absorption.

Inhalation

N-methyl-N-(C18-(unsaturated)alkanoyl)glycine has a vapour pressure of 1.31E-4 Pa at 20 °C. Based on the low vapour pressure value, vapours of the substance 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.

Acute inhalation toxicity studies conducted with aerosols of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine (BASF, 1979b&c) are available. The LC50 for both males and females was 1.37 mg/L air and 2.3 mg/L air, respectively. Clinical signs observed in both studies are considered to be secondary effects due to local irritation of the respiratory tract. Although not classified for respiratory irritation the substance is well-known for its effects on the respiratory tract as confirmed by its self-warning ability (instantly induces coughing) well-known from handling experience.

Overall, taking the physico-chemical parameters and the acute inhalation toxicity data into consideration, respiratory absorption of N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is assumed to be possible, but expected to be rather low.

Distribution/Accumulation

The distribution of the structural analogue Sodium N-lauroylsarcosinate was investigated in the oral absorption study mentioned above where [14C]Sodium lauroyl sarcosinate 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 lauroyl sarcosinate. 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

In the oral absorption study described above, where [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 N-methyl-N-(C18-(unsaturated)alkanoyl)glycine is by urinary excretion.