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Description of key information

The physicochemical properties of the test item allow systemic absorption following oral and dermal uptake, but study results have demonstrated that systemic effects are secondary to the local effects caused by the substance. As the molecules are highly water-soluble, the rate of diffusion across membranes could limit their distribution and the extracellular concentration is supposed to be higher than the intracellular concentration. The molecules will most probably not cross the blood-brain barrier, which is confirmed by the test results not indicating distribution to the CNS. Local effects observed probably result from the reactive quaternary ammonium cation. Based on the structure of the molecule it can be assumed that the substance undergoes oxidation reactions of the alkyl side chain, forming ketones and hydroxyketones, to render the molecules more polar. The substance is supposed to be mainly excreted via faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetics of “Mixture of dodecyltrimethyl ammonium chloride (C12 derivative), tetradecyltrimethyl ammonium chloride (Myristyl derivative), hexadecyltrimethyl ammonium chloride (Cetyl derivative)”

Toxicological profile

In the acute oral toxicity study the LD50 was determined to be 207 mg/kg bw in rats.

For testing the acute dermal toxicity the test item was applied as aqueous solution (33 % w/w) to the skin of male and female New Zealand White rabbits. The LD50 was determined to be 429 mg/kg bw.

For testing the compound for its local effects on skin, 0.5 mL of the test item (40 % active ingredient as an aqueous solution) was applied to 6 New Zealand White rabbits and remained on the skin under semi-occlusive covering for 4 hours. Afterwards, the skin reactions were recorded daily. The test material as well as the active ingredient were determined to be corrosive to the skin. In an acute eye irritation study the test material (containing 33 % active ingredient in an aqueous solution) was found to be severely irritating to the eyes of New Zealand White rabbits. A skin sensitization assay (Bühler Test with Dunkin-Hartley Guinea pigs) revealed that the test material was not skin sensitising. In a chronic oral repeated dose toxicity study using Beagle dogs the read across-substance DDAC only produced mild changes in clinical pathology parameters in the high dose group (20 mg/kg bw). The NOAEL for systemic effects was found to be 10 mg/kg bw day. For local effects, the NOAEL was determined to be 3 mg/kg bw/day. In a 2 weeks skin irritation study a NOAEL of 6 mg/kg be/day was derived for local effects on the skin. Additionally, data obtained with the test substance itself are also available. In a 90-day repeated dose oral toxicity study with rats a NOAEL of 100 ppm, which is equivalent to 22 mg/kg bw/day, was revealed. No indications of target organ toxicity were found in these studies.

A study on reproductive toxicity was not conducted as a developmental toxicity study (OECD 414) conducted on rats with the read-across substance DDAC is available. The NOEL for maternal toxicity was found to be 0.81 mg/kg bw/day and the NOEL for developmental toxicity was determined to be 16.2 mg/kg bw/day in this study.

The test item was tested in three in vitro studies to assess its genetic toxicity: a bacterial reverse mutation assay, a chromosome aberration assay using mammalian cells and an in vitro mammalian cell gene mutation assay were performed. All results were negative with and without metabolic activation and therefore the test substance was found to be not mutagenic and not clastogenic.

 

Toxicokinetic analysis of “Mixture of dodecyltrimethyl ammonium chloride (C12 derivative), tetradecyltrimethyl ammonium chloride (Myristyl derivative), hexadecyltrimethyl ammonium chloride (Cetyl derivative)”

The test substance is a solid which is manufactured and supplied as aqueous solution. Its molecular weight (range 207.8-348.1 g/mol) depends on the composition of molecules containing carbon chains of different length (C8-C18, even-numbered, with C12, 14, 16 being the most frequent ones).The solid material has a low vapour pressure of 1.8 x 10-6 Pa, 20°C and a high water solubility of 346 g/L at pH 7 and 20°C. No value for partition coefficient has been or can be experimentally determined or modeled. The test substance is essentially miscible in water and octanol. Therefore, the best estimate of partition coefficient, although such an estimate is not considered useful, is 1 (log Kow = 0).

 

Absorption

Quaternary ammonium substances are poorly absorbed, but systemic effects are possible after all routes of exposure (INCHEM 2009), but were in this case secondary to the irritant effects caused by the test compound.

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, the high water solubility enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Taken together, the physiochemical properties indicate that the substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity studies. The acute oral toxicity study in Sprague-Dawley rats revealed an LD50 value of 207 mg/kg bw.

Due to the low vapour pressure of the test substance it is unlikely that it will be available as a vapour, but if it is the case absorption via inhalation route is possible as absorption following ingestion did also occur. The water solubility would enable dissolving in the mucus lining of the respiratory tract. As the molecules might be too large to be absorbed through aqueous pores and also exhibit hydrophilic properties, uptake at high rates directly across the respiratory tract epithelium by passive diffusion is not likely. With regard to the skin corrosive property of the test substance on the other hand it is likely that some reactions would occur on the site of contact and modify the absorption rate.

According to “Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance” (ECHA, 2008) dermal uptake of quaternary ammonium ions is slow due to their reactivity and binding to skin components. But dermal absorption will in this case take place to a considerably extent, as was demonstrated by the acute dermal toxicity study conducted with New Zealand White rabbits revealing a LD50 value of 429 mg/kg bw. Dermal absorption is supposed to be favoured by the water solubility and also by the size of the molecules.

 

Distribution

As mentioned above, the physicochemical properties of the test item allow systemic absorption following oral and dermal uptake. As the molecules are highly water-soluble, the rate of diffusion across membranes could limit their distribution and the extracellular concentration is supposed to be higher than the intracellular concentration. They will most probably not cross the blood-brain barrier, which is confirmed by the test results not indicating distribution to the CNS. Repeated dose toxicity studies did not demonstrate toxicity to specific organs or tissues after oral absorption. No test item related abnormalities were found during necropsy. In contrast to that, after single administration of higher doses in the acute toxicity studies the kidneys, adrenal glands, brain, liver and intestines were found to appear abnormal due to reddening in Sprague-Dawley rats after oral administration. The brain and thymus were found to be haemorrhagic and dark red areas were observed in the stomachs of New Zealand White rabbits that had died after dermal application. These findings indicate that the molecules might be distributed in the body through the bloodstream. Furthermore the haemorrhagic organs and glands demonstrate that blood is leaking out of the vessels due to damage of the capillary endothelium. This damage is presumably caused by lipid peroxidation taking place between the cationic molecules and membrane lipids.

 

Metabolism

No data on metabolism of the test substance is available. Bioaccumulation is not expected.

Based on the structure of the molecule it can be assumed that the substance undergoes oxidation reactions of the alkyl side chain, forming ketones and hydroxyketones, to render the molecules more polar. Due to the molecules already being highly hydrophilic, further conjugation reactions are not to be expected. Due to their polarity and relatively high molecular weights, the molecules are not supposed to undergo enterohepatic circulation.

 

Excretion

The majority of the quaternary ammonium compound will be excreted via faeces after ingestion (INCHEM 2009), as the size of the molecule does not favour renal excretion.

 

Summary

As a conclusion signs of systemic toxicity as changes in organs or effects on reproduction, development, mutagenicity, carcinogenicity, neurobehavior or other key toxicological endpoints were not exhibited. The effects observed in toxicity studies have only become present at irritant doses and general effects, including body weight changes at lower doses and death at high doses, are secondary to these irritant responses. Local effects observed probably result from the reactive quaternary ammonium cation. The substance is supposed to be metabolized by oxidation reactions and mainly excreted via faces.

 

 

References

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

INCHEM (2009) Quaternary Ammonium. International Programme on Chemical Safety (IPCS) INCHEM.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.

 

Mutschler E., Schäfer-Korting M. (2001). Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2001

 

ECETOC Guidance (2002) Recognition of and Differentiation between, Adverse and Non-adverse effects in Toxicoloigal studies. Technical Report No. 85.