Quaternary ammonium compounds, tri-C8-10-alkylmethyl, chlorides

Endpoint summary

Description of key information

Due to the log Pow of 2.93, the good water solubility and the relatively high molecular weight, only some uptake by passive diffusion is expected after oral exposure or inhalation. Due to the corrosivity a dermal uptake of 100% is expected for the undiluted substance. An in vivo dermal absorption study conducted with a structural homologue (please refer to ch. 13 for read-across justification) points to a poor uptake through the skin at non-corrosive concentrations. Once absorbed, the substance is assumed to be efficiently metabolized by Phase I and Phase II metabolic enzymes (oxidative N-dealkylation followed by conjugation to glucuronate) and excreted via bile.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

1.     Chemical and physico-chemical description of the substance

The target substance can be described as quaternary ammonium compounds, tri-C8-10-alkylmethyl, chlorides (CAS 63393-96-4).

It consists of an alkylated ammonium ion and a chloride ion. Of the four alkyl chains attached to the positively charged nitrogen, one is a methyl group. The other three alkyl chains are either octyl or decyl groups. According to the analytical investigations, the following three major components / one minor component are present:

~ 40% Decyl-methyl-dioctyl-ammonium chloride

~ 24% Methyl(trioctyl)ammonium chloride

~ 22% Didecyl-methyl-octyl-ammonium chloride

~ 4% Tris-decyl(methyl)ammonium chloride

These three major and one minor components account for approx. 96% of the substance. Other non-specified impurities are present at a concentration of <4% altogether. In conclusion, the substance can be regarded as relatively homogenous, as the single components only differ in C2-units of the alkyl chains (C8 or C10).

Description of the physico-chemical properties:

- physical state (20°C): viscous liquid

- vapour pressure (20°C): 0.0123 Pa

- molecular weight: appr. 404 Da (trioctyl component)

- log Pow: 2.93

- water solubility: 1023 mg/L at 20 °C (experimental data)

- boiling point: substance decomposes at about 158.5°C

The substance is characterized by ionic nature and a negligibly low volatility. Despite a moderate log Pow (2.93), the target substance shows good water solubility.

 

2.    Toxicokinetic assessment

No experimental data on absorption, metabolism, distribution and excretion are available for the substance. Therefore, the toxicokinetic behavior was evaluated based on the structure and the physico-chemical properties of the substance.

 

2.1 Absorption:

As the target substance is ionized, therefore it will not readily diffuse across biological membranes. The molecular weight of approximately 404 Da implies a moderate absorption potential after oral intake, but a passage through aqueous pores or the epithelial barrier by the bulk passage of water is only favorable for substances with a molecular weight of less than 200 Da. The Log Pow of 2.93 is favorable for passive diffusion, thus some oral uptake can be expected. With a water solubility of 1023 mg/L, the target substance is assumed to dissolve in the gastrointestinal fluid. In the acute oral toxicity study available for the substance, a LD50 of 200-2000 mg/kg was deduced. However, the effects appeared at the site of contact and were attributed to the corrosive potential of the substance. The corrosivity is assumed to enhance penetration. In a repeated dose toxicity study (combined with the reproduction / developmental toxicity test) in rats the substance caused signs of systemic toxicity (decreased food consumption and decreased body weight parameters), revealing that absorption has occurred. However, apart from that, no specific data concerning oral absorption of the test substance are available. Therefore, as a worst case an oral absorption of 100 % is assumed.

With regard to absorption after inhalation, the target substance has a low vapour pressure of 0.0123 Pa and the boiling point is > 158.5 °C (due to the decomposition of the substance at 158.5°C an exact value cannot be determined), indicating that inhalation as a vapour will be negligible. If the substance reaches the respiratory tract, some passive diffusion is likely due to the log Pow of 2.93 but the rather high molecular weight will limit the amount taken up. Because of the good water solubility, the substance is likely to dissolve in the mucus of the upper respiratory tract, and consequently will at least partly be removed before reaching the lower respiratory tract. Due to the lack of data as a worst case 100 % absorption after inhalation is assumed as well.

The relatively high molecular weight (appr. 404 Da for the trioctyl component) and especially the ionic nature suggests a limited dermal uptake at non-corrosive concentrations. Substances containing ammonium groups are known to bind to skin components, which reduces the dermal absorption. It can be assumed that the log Pow of 2.93 limits the entrance into the stratum corneum, thus the bioavailability after dermal contact will be limited at non-corrosive concentrations. An in vivo study for dermal absorption is available for the structural homologue DODMAC (dimethyldioctadecylammonium chloride, CAS 107-64-2). The substance (10 mg of (≈30μCi) 14C-labelled DODMAC) was applied to the back of each of four rabbits over a 5 - 8 cm area. As measured by the recovered amount of radioactivity, most of the substance remained at the site of application (88 ± 2.3%). Only traces of the administered radioactivity were detected in urine (0.15 %), faeces (0.16 %), exhaled carbon dioxide (0.27 %), other skin (0.2%) and cage wash (0.3%) over a 72 h-period (Drotman, 1977). On the basis of this test with a structural homologue and the implications from structure, PC data and the skin corrosion test, a dermal uptake of 100 % is expected for the undiluted substance. At non-corrosive concentrations, where the skin barrier is not destroyed, dermal uptake however will be low.

2.2 Metabolism and Excretion:

The part of the target substance that is systemically available is expected to undergo a N-dealkylation reaction (Phase I metabolism) in which the methyl group can be removed. The resulting metabolite could then be linked to a glucuronate, catalyzed by the enzyme UDP-glucuronosyltransferase (UGT). The formation of quaternary ammonium-linked glucuronides by the human UGT1.4 protein was demonstrated for pharmaceuticals (e.g. M.D. Greene et al., Drug Metabolism and Disposition, 1995). The conjugated metabolites are assumed to be excreted mainly via bile, as suggested by the molecular weight > 500 Da. The target substance as such could in principle be excreted via urine, because of the smaller size and the already good water solubility of the parent compound.

After dermal exposure, the target substance is not expected to penetrate the stratum corneum at a large extent at non-corrosive concentrations. Consequently, it will be removed with the exfoliation of the skin or in the sweat.

A bioaccumulation potential is not expected, considering the physico-chemical properties and the mechanisms for excretion of the target substance and potential metabolites.