Docosyltrimethylammonium methyl sulphate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Data on supporting substances (see below): limited absorption in adult rats (<= 10%) after oral administration
Short description of key information on absorption rate: 
Read-Across: In vitro skin penetration study (OECD TG 428)  with docosylrimethylammonium chloride (C22-ATQ) on human skin: maximum absorption 0.20 +/- 0.20% of applied dose.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

0.5

Additional information

The toxicokinetic profile of a substance comprises its absorption into the body, its distribution in the body, its metabolism in the body and its excretion from the body. Taking into account the physicochemical properties and the toxicological test results, qualitative estimates for these aspects may be deduced for docosyltrimethyl ammonium methosulfate.

 

Absorption: a prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. Docosyltrimethyl ammonium methosulfate has a low solubility in water (although at concentrations >7 mg/L it will form a colloidal dispersion of micelles, which, however, are too large to be taken up directly) and a considerable solubility in n-octanol. Therefore, it is likely that docosyltrimethyl ammonium methosulfate becomes systemically bioavailable to a certain extent after oral, dermal or inhalation exposure.

In in vivo studies in rats with the analogous substances [¹⁴C]didecyldimethyl ammonium chloride (BTC, 1989) and namely [1-¹⁴C]cetyl trimethyl ammonium bromide (Isomaa, 1975) about 90% of the orally administered dose was excreted via the faeces. The data indicate that about 10% of the administered dose becomes systemically bioavailable.

The in vitro percutaneous absorption of the structurally similar substance C22-Trimethylammonium chloride (C22-ATQ) through human skin membranes was evaluated in flow-through diffusion cells according to OECD TG 428 following application in two relevant in use formulations, i.e.in a rinse-off hair care product (a cream rinse) at a concentration of 5% (w/w) and in a leave-on skin cream product (a cationic O/W cream) at a concentration of 3% (w/w). The mean total absorption of C22-ATQ from the 5% cream rinse formulation after 24 h was 0.20 +/-0.20% of the dose applied. The mean total absorption of C22-ATQ from the 3% Cationic O/W Cream after 24 h was 0.16+/-0.08% of the dose applied.

This study is considered to be relevant for the submission substance due to its quality, the use of human skin and because the tested substance differs from the submission substance only in the purity and in the anion. Therefore, based on the highest observed absorption value from this key study (0.2%) a conservative value of 0.5% is derived for risk characterisation purposes in this registration dossier.

The likelihood for inhalation exposure is low due to the very low vapour pressure of docosyltrimethyl ammonium methosulfate. In the unlikely event of exposure to aerosolized substance in respirable form, absorption of the substance deposited in the respiratory tract is considered likely.

Distribution: the distribution of the analogous substance dodecyltrimethyl ammonium bromide was measured after a single intravenous injection of radiolabeled [¹⁴C]dodecyltrimethyl ammonium bromide into rats (Bartnik and Wingen, 1979). Radioactivity levels in the blood decreased rapidly. The percentages of administered radioactivity in individual organs after 15 min and 24 h were 24.8% and 2.08% in liver, 5.54% and 0.36% in kidneys, 0.48% and 0.11% in heart, 0.15% and 0.11% in spleen, 0.83% and 0.14% in lungs, not detectable and 1.41% in intestinal tract and 1.47% and not detectable in blood. There was no sign of accumulation of radioactivity in any organ. From these results it can be concluded that docosyltrimethyl ammonium methosulfate will distribute via the blood to several organs in the body (with highest concentrations in the liver and kidneys), but will not bioaccumulate in any specific organ.

 

Metabolism: In toxicokinetic studies, rats received a single oral gavage administration of analogous substances, namely [1-¹⁴C]cetyl trimethyl ammonium bromide in water (0.8 mg/kg) (Isomaa, 1975) or [¹⁴C]didecyldimethyl ammonium chloride in water (50 mg/kg) (BTC, 1989). Thin layer chromatography of bile and urine indicated that most of the absorbed cetyl trimethyl ammonium bromide was probably metabolized (due to limited amounts, identification of metabolites was not possible). Metabolism of didecyldimethyl ammonium chloride comprised the oxidation of the two decyl side chains to form hydroxy and hydroxyketo derivatives (more metabolism in females compared to males). Metabolism of methyl side chains was not found. The authors speculated that gut microbial activity may have been responsible for the metabolism, however, Isomaa (1975) found no indication of metabolism when cetyl trimethyl ammonium bromide was incubated with fecal homogenates and urine. From these results it can be concluded that docosyltrimethyl ammonium methosulfate will be metabolized through alkyl side chain oxidation.

Excretion: In toxicokinetic studies, rats received several analogous substances. After a single intravenous injection of radiolabeled [¹⁴C]dodecyltrimethyl ammonium bromide (Bartnik, 1979), rats eliminated most radioactivity within 24 h from the body via the kidneys (58.9%) and feces (11.6%). After a single oral gavage administration of [1-¹⁴C]cetyl trimethyl ammonium bromide rates excreted 92% of the radioactivity in feces (2% excreted into bile in the first 12 h) and about 1% in urine and exhaled no radioactivity into breathing air within 3 days (Isomaa, 1975). After a single oral gavage administration of [¹⁴C]didecyldimethyl ammonium chloride (BTC, 1989), rats excreted the radioactivity primarily via feces (89-99%) and urine (2.5%), with an insignificant amount in the expired air. From these results it can be concluded that after oral administration docosyltrimethyl ammonium methosulfate will be excreted in feces at >90% (mostly unabsorbed parent substance), while only a small percentage will be excreted in urine.

Discussion on bioaccumulation potential result:

Data on supporting substances:

In a toxicokinetic study (BTC, 1989, as cited in secondary sources CDRP and RMS Italy), rats received a single oral gavage dose of 14C-labelled didecyldimethyl ammonium chloride. The majority (>90% ) of the administered dose was excreted via the faeces. From the amount excreted in urine (<3%) and tissue residues (<1%), the report authors concluded that the oral absorption was less than 10%.

In a toxicokinetic study (Isomaa, 1975), female rats received a single oral gavage administration of 0.8 mg/kg [1-14C]cetyltrimethyl ammonium bromide in water. After 3 days 92% of the dose was excreted in feces and about 1% in urine. About 85% of the radioactive substance excreted in feces after 3 d was the parent compound. About 2% of the administrated radioactivity was excreted in the bile during the first 12 hours after treatment. Taken together, these data indicate that about 10% of the administered dose was absorbed. Only small amounts of radioactivity were found in the blood and organs. Highest peak concentratons (at 4-8 h) were found in liver (about 0.8% of administered radioactivity) and lower levels in kidneys, spleen, heart, lung and skeletal muscle.

After a single intravenous injection of radiolabeled [14C]dodecyltrimethyl ammonium bromide into rats, most radioactivity was eliminated within 24 h from the body via the kidneys (58.9%) and feces (11.6%) (Bartnik and Wingen, 1979). Radioactivity levels in the blood decreased rapidly. The percentage of administered radioactivity in the liver and kidneys was 24.8% and 5.54%, respectively, after 15 minutes and 2.08% and 0.36%, respectively, after 24 hours. Only small amounts of radioactivity were found in other organs and there was no sign of accumulation of radioactivity in any organ.

Discussion on absorption rate:

The in vitro percutaneous absorption of the structurally similar substance C22-Trimethylammonium chloride (C22-ATQ) through human skin membranes was evaluated in flow-through diffusion cells according to OECD TG 428 following application in two relevant in use formulations, i.e.in a rinse-off hair care product (a cream rinse) at a concentration of 5% (w/w) and in a leave-on skin cream product (a cationic O/W cream) at a concentration of 3% (w/w). The contact time was 30 minutes for the rinse-off product and 24 hours for the leave-on product. In addition to the amount of radiolabel in the receptor fluid, the residues remaining in/on the skin membranes and in the stratum corneum were determined. The mean total absorption of C22-ATQ from the 5% cream rinse formulation after 24 h was 0.20 +/-0.20% of the dose applied. The mean total absorption of C22-ATQ from the 3% Cationic O/W Cream after 24 h was 0.16+/-0.08% of the dose applied.

This study is considered to be relevant for the submission substance due to its quality, the use of human skin and because the tested substance differs from the submission substance only in the purity and in the anion. Therefore, based on the highest observed absorption value from this key study (0.2%) a conservative value of 0.5% is derived for risk characterisation purposes in this registration dossier.