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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, C12-18 (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 C12-18 AAAO hereafter, is a UVCB substance with a water solubility of 1.05 g/L (at 20°C ), a moderate log Pow (1.27 at 20°C) and a vapour pressure of 60 Pa at 20°C. C12-18 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; at most acidic and most basic temperature resp.). The substance is classified as acute oral toxicant category 4 (H302) (LD50 >= 500 - <=1000 mg a.i./kg bw). The substance is classified as a skin irritant category 2 (H315) based on a conservative approach, due to its purity/concentration of 79% and since no data is available on the pure substance. Based on a weight-of-evidence approach, the substance is classified as Eye Damage 1 (H318) according to the CLP Regulation. The substance is not considered to be a skin sensitiser.


 


Absorption


Oral/GI (gastrointestinal) absorption:


As per the substance water solubility (1.05 g/L), C12-18 AAAO is expected to readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or will be carried through the epithelial barrier by the bulk passage of water.


The moderate log Pow (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.


C12-18 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 C12-18 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 C12-18 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.


C12-18 AAAO has been tested in an acute oral toxicity study, a 28-day oral repeated dose toxicity study, a 90-day oral repeated toxicity study, a screening test for reproductive effects, prenatal developmental toxicity studies and an EOGRTS, all of them in rats (apart from one of the PNDT studies) and using water as a vehicle. Compounds delivered in aqueous media are likely to be absorbed.


In an acute oral toxicity study (Sanders, 2000a), clinical adverse signs in animals treated with 2174 mg/kg bw (equivalent to 2000 mg/kg bw a.i.) were observed. All animals treated with 218 mg/kg (200 mg/kg bw a.i.) appeared normal throughout the study. Macroscopic observations in animals that during the study (treated with 2174 mg/kg bw) 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), C12-18 AAAO was tested at 15, 150 and 1000 mg a.i./kg bw/day.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 bw/day.


Daily oral administration of Amides, C12-18 AAAO 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 bw/day, resulted in toxicologically significant effects at dose levels of 500 mg/kg bw/day and 150 mg/kg bw/day. The observed changes in the (fore)stomach, urinary bladder and red blood cell parameters at 500 mg/kg bw/day and the changes in the (fore)stomach at 150 mg/kg bw/day were considered adverse and toxicologically significant. No adverse effect was observed at 50 mg/kg bw/day. Therefore, the NOAEL was set at 50 mg/kg bw/day.


Oral administration of the test substance to rats for a period of up to 54 consecutive days at dose levels of up to 100 mg a.i./kg bw/day in a Reproduction/Developmental toxicity screening test (Marr (2010); according to OECD guideline 421), did not result in any treatment-related effects. The No Observed Effect Level (NOEL) for systemic toxicity and reproductive toxicity was therefore considered to be 100 mg/kg bw/day (incorporating a correction factor for 31.8% purity).
Daily oral (gavage) administration of 712.5, 1425, or 1995 mg/kg bw/day (equivalent to 250, 500, or 700 mg a.i./kg bw/day) of the test substance from GD 6 - 20 to pregnant female rats in a Prenatal Development Study (Barraclough (2021); according to OECD guideline 414), resulted in test article‑related effects at all dose levels. As such, 250 mg/kg bw/day AI is considered to represent the no observed adverse effect level (NOAEL) for maternal animals and prenatal development of the subsequent offspring.

Daily oral (gavage) administration of 142.5, 356.25 or 498.75 mg/kg bw/day test substance (equivalent to 50, 125, or 175 mg a.i./kgbw/day) from GD 6 - 28 to pregnant female rabbits in a Prenatal Development Study (Barraclough (2021); according to OECD guideline 414), resulted in test article-related effects, including mortality and a single abortion following administration of 175 mg a.i./kg bw/day. As such, 175 mg a.i./kg bw/day was considered adverse. Test article-related effects following administration of 125 mg a.i./kg bw/day were confined to non-adverse effects and were considered to be attributable to the maternal effects and not a direct effect on fetal development, as these changes did not adversely affect the growing fetus. The no observed adverse effect level (NOAEL) for maternal toxicity was established as 125 mg a.i./kg bw/day. The NOAEL for developmental toxicity was established as 125 mg a.i./kg bw/day.


Once-daily oral gavage administration of 142.5, 285, or 427.5 mg/kg bw/day (equivalent to 50, 100, or 150 mg a.i./kg bw/day) test substance in an extended one-generation reproductive toxicity study (EOGRTS; Barraclough (2021); according to OECD 443), to Han Wistar rats for 10 weeks prior to pairing, throughout pairing, during gestation, and throughout lactation for females, and then administered to the F1 offspring until adulthood, resulted in test article‑related effects at all dose levels investigated. Test article-related effects consisted of clinical observations noted after dosing, which were attributable to test article palatability and did not represent systemic toxicity. Changes in red cell parameters were also observed, together with an increased incidence and/or severity of extramedullary hemopoiesis and pigmented macrophages in the spleen, which corresponded with incidences of large spleens and increased spleen weights. These findings, however, did not have an impact on the overall health of the animals; as such, the no observed adverse effect level (NOAEL) for systemic toxicity is 150 mg a.i./kg bw/day. No adverse effects on mating performance, fertility, fecundity, gestation, parturition, or lactation were noted; as such, the no observed effect level (NOEL) for reproductive toxicity is 150 mg a.i./kg bw/day in this study. No effects on the developing offspring was noted at any dose level; as such, the NOEL for offspring growth and development is 150 mg a.i /kg bw/day.


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


Respiratory absorption:


Given the fact that the vapour pressure is lower than 500 Pa and the boiling point (126.4 °C) is close to 150 °C, C12-18 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, C12-18 AAAO may be retained within the mucus, and subsequently absorption by passive diffusion may occur based on its solubility and moderate log Pow 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.


C12-18 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 irritating 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 C12-18 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 conservative approach.


Dermal absorption:


In view of the substance water solubility (1.05 g/L; between 100-10,000 mg/L), penetration into the lipid-rich stratum corneum will be hampered and hence dermal absorption is expected to be limited.


Dermal absorption is favoured as the log Pow 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 Pow.  


C12-18 AAAO has surface active properties and this could enhance the potential for dermal uptake.  


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


In an acute dermal toxicity study (Sanders, 2000b), C12-18 AAAO was tested at 2000 mg a.i./kg bw 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 via the dermal route (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 bw. 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 bw. 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 Pow 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 C12-18 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 Pow and the relatively high water solubility, C12-18 AAAO is not expected to accumulate easily in the body (lung, adipose tissue, stratum corneum).


Metabolism


Once absorbed, C12-18 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 C12-18 AAAO occurs at the hepatic level.


Excretion


Given the relatively high water solubility, C12-18 AAAO and its metabolites are expected to be excreted mainly via the urine. Small amounts of C12-18 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


-Barraclough (2021): Amides, C12-18 (even numbered), N-[3-(dimethylamino) propyl], N'-oxides: Oral (Gavage) Administration Prenatal Development Study in the Rat (OECD 414, adopted 25 June 2018). Covance Laboratories Ltd (Technical report)


-Barraclough (2021): Amides, C12-18 (even numbered), N-[3-(dimethylamino) propyl], N'-oxides: Oral (Gavage) Administration Prenatal Development Toxicity Study in the Rabbit (OECD 414, adopted 25 June 2018). Covance Laboratories Ltd (Technical report)


-Barraclough (2021): Amides, C12-18 (even numbered), N-[3- (dimethylamino) propyl], N'-oxides: Oral (Gavage) Extended One-Generation Reproductive Toxicity Study in the Rat (OECD 443). Covance Laboratories Ltd (Technical report)


-Horne C (2014): Amides, C12-18 (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)


-Marr A (2010): Amides, C12-18 (even numbered), N-[3- dimethylamino) propyl], N’-oxides oral (gavage) Reproduction/Developmental Toxicity Screening Test in the rat. Harlan Laboratories Ltd (Technical report)


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


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