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Description of key information

No toxicokinetic data (animal or human studies) are available on this substance. This assessment is based on physico-chemical parameters and other available information (e.g., toxicological data) and will allow a qualitative assessment of the toxicokinetic behaviour of Amides, C12-C18 (even numbered), N-[3- dimethylamino) propyl], N’-oxides.

The physico-chemical properties used are in general applicable for pure substances only. Hence the (physico-chemical properties) values used in the current assessment are best estimates aiming to describe the intrinsic properties of the UVCB substance as a whole. As a consequence, compounds with a (significantly) different behaviour might be present in the mixture. The results of this toxicokinetic assessment should therefore be treated with care.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Amides, C12-18 (even numbered), N-[3-(dimethylamino) propyl], N'-oxides, named also C12-C18 AAAO hereafter, is a UVCB substance with a water solubility of 1.05 g/L (at 20°C ), a moderate log P (1.27) and a vapour pressure of 60 Pa at 20°C. C12-C18 AAAO has surface active properties (35.0 mN/m; 1g/L; 20°C). The pKa values for this UVCB were estimated to be 15.91 and 4.7 (calculated with the ACD/I-lab software). The substance is found to be irritating to skin. The substance is not considered to be a skin sensitiser.

Absorption

Oral/GI (gastrointestinal) absorption:

As per its water solubility, C12-C18 AAAO will readily dissolve into the gastrointestinal fluids and subsequently will pass through aqueous pores or will be carried through the epithelial barrier by the bulk passage of water.

The moderate log P (between -1 and 4) is favourable for absorption by passive diffusion.

At the pH of the intestinal tract, the substance is expected to be partially ionised. Therefore the absorption by passive diffusion will be hampered for the ionized proportion.

C12-C18 AAAO has surface active properties and the substance can therefore form micelles. Micellar solubilisation can enhance absorption. The impact of the surface active properties on the oral absorption rate of C12-C18 will depend on the concentration to which the different components of this UVCB substance form micelles as well as the type of formed micelles (e.g. anionic, cationic, non-ionic). No information is available in this matter but, based on surface active properties of C12-C18 AAAO as a whole, it is concluded that the substance may be absorbed to some extent in the GI tract.

The substance has skin irritating properties and therefore it could enhance penetration by local damage of GI tissues.

C12-C18 AAAO has been tested in an acute oral toxicity study, a 28-day oral repeated dose toxicity study and a 90-day oral repeated toxicity study, all of them in rats and using water as a vehicle. Compounds delivered in aqueous media are likely to be absorbed.

In an acute oral toxicity study (Sanders, 2000), clinical adverse signs in animals treated with 2174 mg/kg (equivalent to 2000 mg pure test material/kg) were observed. All animals treated with 218 mg/kg appeared normal throughout the study. Macroscopic observations in died animals during the study (treated with 2174 mg/kg) were haemorrhagic lungs, dark liver, dark kidneys, haemorragic gastric mucosa, sloughing and/or haemorrhage of the non-glandular epithelium of the stomach and haemorrhagic small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study. The above-mentioned toxicological findings, especially coloured organs, may indicate absorption of the test substance to some extent (qualitative observation).

In a 28-day repeated oral dose toxicity study (Jones et al., 2000) C12-C18 AAAO was tested at 15, 150 and 1000 mg/kg bw/day doses.

Animals treated at 1000 mg/kg bw/day showed clinically observable signs of toxicity (e.g. hunched posture, increased salivations, fur loss) from day 3. No toxicologically relevant signs of toxicity were observed at the mid and low doses. Histopathological evaluation revealed treatment-related changes in liver (centrilobular hepatocyte enlargement), spleen (extramedullary haemopoiesis), kidneys, urinary bladder (hyperplasia of the transitional cell epithelial lining) and stomach. The above-mentioned toxicological findings indicate that absorption of the test substance occurs. This assumption is also supported by elevations in plasma aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and bilirubin in animals treated at 1000 mg/kg bw/day and 150 mg/kg bw/day.

The NOEL was set at 15 mg/kg/day.

Daily oral administration of Amides, C12-C18 (even numbered), N-[3- dimethylamino) propyl], N’-oxides to Sprague-Dawley rats for 13 weeks (Horne (2014); test performed according to OECD 408) at dose levels of 50, 150 and 500 mg/kg/day, resulted in toxicologically significant effects at dose levels of 500 mg/kg/day and 150 mg/kg/day. The observed changes in the (fore)stomach, urinary bladder and red blood cell parameters at 500 mg/kg/day and the changes in the (fore)stomach at 150 mg/kg/day were considered adverse and toxicologically significant. No adverse effect was observed at 50 mg/kg/day. Therefore the NOAEL was set at 50 mg/kg/day.

The oral absorption factor is set to 100%, based on the above-mentioned information. The results of the toxicity studies do not provide reasons to propose another value.

Respiratory absorption:

Given the vapour pressure lower than 500 Pa and the boiling point (126.4 °C) close to 150 °C, C12-C18 AAAO is not considered to be a volatile substance and the availability for inhalation as a vapour is expected to be limited.

Once in the respiratory tract, C12-C18 AAAO may be retained within the mucus, and subsequently absorption by passive diffusion may occur based on its solubility and moderate log P value (between -1 and 4) .

At biologically relevant ph (e.g; 7), the substance is expected to be partially ionised. Therefore the absorption by passive diffusion will be hampered for the ionized proportion.

C12-C18 AAAO has surface active properties and may be absorbed to some extent at GI tract level . For absorption of potentially deposited material into the lungs, similar behaviour as for the absorption through the GI tract would be expected. It is therefore likely that the substance will also be absorbed if it is inhaled.

The substance is irritant to the skin. Therefore it could enhance penetration by local damage at the respiratory tract level.

No inhalation repeated dose toxicity study is available for the substance.

Toxicity was observed when C12-C18 AAAO was administered by oral gavage in a 28 -day (Jones et al., 2000) and in a 90-day repeated dose toxicity study (Horne, 2014). For absorption of potentially deposited material into the lungs, similar behaviour as for the absorption through the GI tract would be expected. It is therefore likely that the substance will also be absorbed if it is inhaled.

Based on the above considerations, the inhalatory absorption factor is set to 100%, as a worst case assumption.

Dermal absorption:

In view of its water solubility (100-10,000 mg/L), penetration into the lipid-rich stratum corneum will be hampered and hence dermal absorption might be limited.

Dermal absorption is favoured as the log P of the substance is between 1 and 4 indicating sufficiently lipophilic to cross the stratum corneum.

Partition from the stratum corneum into the epidermis after penetration will be enhanced due to the water solubility but hampered by the moderate log P.

C12-C18 AAAO has surface active properties and this could enhance the potential for dermal uptake.

The substance is irritant to skin and therefore penetration could be enhanced by local damage.

In an acute dermal toxicity study (Sanders, 2000), C12-C18 AAAO was tested at 2000 mg/kg in rats, unchanged and using a semi-occlusive type of coverage. After a 14-day observation period, no test substance related effects were noted from clinical observations or post-mortem examination. These observations were made only after single exposure but they may be an indication of low absorption of the test substance (qualitative observation).

No mortality or systemic effects were reported by the dermal route in the above-mentioned acute toxicity study at the dose level of 2000 mg/kg. At the same dose level, mortality and clinical signs were reported in an acute toxicity study in rats by oral route but not at a dose level of 200 mg/kg. This 10-fold difference is a rough indication of differences in absorption between the oral and dermal route. It could therefore be expected that dermal absorption is about 10-fold lower than oral absorption.

No dermal repeated dose toxicity study is available for the substance.

Generally, default values of 10% and 100% are used for dermal absorption (ECHA guidance on IR&CSA, R.7c). Based on the available information on acute toxicity, 10% is proposed as dermal absorption factor.

 

Distribution

The relatively high water solubility predicts that the substance will be distributed widely through the body.

Based on the moderate log P and the water solubility, the substance is expected to distribute poorly into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

A 28-day oral repeated dose toxicity study (Jones et al., 2000) revealed treatment-related changes in liver, spleen, kidneys and urinary bladder. In A 90-day oral repeated dose toxicity study (Horne, 2014), the target organs identified were lung, liver, spleen, (fore)stomach and urinary bladder.

Based on the above-mentioned information, it could be assumed that C12-C18 AAAO is distributed through the body. The results of the studies do not provide reasons to deviate from this assumption.

 

Accumulation

In view of the moderate log P and the relatively high water solubility, C12-C18 AAAO is not expected to accumulate easily in the body (lung, adipose tissue, stratum corneum).

 

Metabolism

Once absorbed, C12-C18 AAAO might undergo phase I biotransformation (including aliphatic hydroxylation) followed by conjugation reactions (phase II) including glucuronidation and sulfation.

The results of the available studies do not provide reasons to deviate from this assumption. Treatment-related histopathological changes (centrilobular hepatocyte enlargement) were observed in a 28-day oral repeated dose toxicity study (Jones et al., 2000) in rats. Centrilobular hepatocyte enlargement is typically a response to hepatic enzyme induction. Therefore, it can be concluded that metabolic transformation of C12-C18 AAAO occurs at the hepatic level.

 

Excretion

Given the relatively high water solubility, C12-C18 AAAO and its metabolites are expected to be excreted mainly via the urine. Small amounts of C12-C18 AAAO are expected to be excreted via faeces.

A 28-day oral repeated dose toxicity study (Jones et al., 2000), revealed treatment-related histopathological changes in kidneys and urinary bladder. Furthermore, histopathological treatment-related changes in urinary bladder were also reported in a 90 -day repeated oral dose toxicity study with this substance. These results support the above assumption.

 

References

Horne C (2014): Amides, C12-C18 (even numbered), N-[3- dimethylamino) propyl], N’-oxides: 13 Week Oral (Gavage) Administration Toxicity Study in the Rat. Covance Laboratories Ltd.

(Technical report)

Jones LJ, Mullee D, Brooks PN (2000): NINOX® HCDO: 28-day repeated dose oral (gavage) toxicity study in the rat. Safepharma Laboratories (Technical report)

Sanders VT (2000): NINOX® HCDO: Acute oral toxicity study in the rat – acute toxic class method. Safepharma Laboratories (Technical report)

Sanders A (2000): NINOX® HCDO: Acute dermal toxicity (limit test) in the rat. Safepharma Laboratories (Technical report)