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Description of key information

Short description of key information on bioaccumulation potential result: see toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There were no experimental studies available in which the toxicokinetic properties of 2-amino-2-ethyl-1,3-propanediol (AEPD) were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of AEPD according to the “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2009)”.

In its pure state, AEPD (119.17 g/mol) is a solid, whereas the commercial product is a transparent, yellow, viscous liquid. However, as there is a manufacturing process in use leading directly to chemical conversion of the solid to the liquid state of AEPD, only the liquid state is of relevance for human health risk assessment. Therefore, all experimental studies were performed with liquid AEPD.

Absorption and distribution

AEPD is highly soluble in water (> 950 g/L), has a low vapour pressure (0.29 Pa) and possesses a relatively low partition coefficient (log Kow = -1.02), resulting in a low potential to accumulate in biological systems.

Acute oral toxicity studies have been conducted in rats and mice. According to OECD 423, a LD50 value of 5000 mg/kg for female rats was calculated (Nishimura, 2004). In this study, no mortality was observed and no clinical signs of toxicity or abnormalities of gross pathology were recorded.

In another oral toxicity study, after dosing of 2500, 3500 and 5000 mg/kg bw and using 10 animals per dose and sex, the mortality was 0, 1, 5 and 5 for the male rats and 0, 1, 2 and 9 for the female rats (Parekh, 1982). Animals found dead during the observation period had severe stomach and intestinal hemorrhage, indicating a local irritating effect of the test substance due to the alkaline pH value. The remaining organs examined grossly appeared normal. The calculated LD50 for females was 3882 mg/kg bw and for males the LD50 was 4571 mg/kg bw, respectively.

A relatively old study (Rubenkoenig, 1955) with mice was also available. The animals were orally administered 1000, 1500, 2000, 3000, 3600 and 4250 mg/kg bw AEPD, using 10 animals per dose level. The mortality was 0, 1, 3, 7, 10 and 10, respectively, by increasing dose. No further data were given. The estimated LD50 was 2470 mg/kg bw.

The findings of the acute oral toxicity studies evidenced that the main cause of acute toxicity was most probably local irritation due to the highly alkaline test substance. With regard to the dose administered and the nature of effects observed, systemic bioavailability of the test substance is considered to be rather low.

In addition, in combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, rats showed no effects on gross pathology. The histopathological examinations displayed reversible effects in the forestomach and corpus. The main cause of these effects was again most probably local irritation due to the highly alkaline test substance administered by gavage.

No data on acute inhalation toxicity are available. As the physical state of AEPD which is relevant for human risk assessment is a liquid and because of its relatively low vapour pressure of 0.29 Pa, inhalation is not considered to be a significant route of exposure. In case of spray applications of technical products containing the neat substance, the concentration is very low (< 1%), therefore the potential for acute toxicity via the inhalation route is considered to be negligible.

The dermal acute toxicity was assessed by exposing rabbits skin to undiluted AEPD (2000 mg/kg bw; pH 11.78) under occlusive conditions (Parekh, 1982). After 24 hours, the skin area was cleaned and the animals were observed for 14 days following administration. No mortality was observed and no clinical signs or unusual findings were noted at necropsy. However, the treated skin areas of all the rabbits were necrotic and oedematous, likely due to the alkalinity of the test substance. The LD50 value was > 2000 mg/kg bw.

For AEPD, a QSAR based modelling published by Potts and Guy (1992), taking into account molecular weight and low Kow, estimated a dermal permeability constant Kp of 6.34E-05 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 60.2 µg/cm²/h AEPD. Usually, this value is considered as indicator for a dermal absorption of 80% (Mostert and Goergens, 2011).As no systemic toxicity was found in the acute dermal toxicity study up to 2000 mg/kg bw, it is expected that systemic bioavailability of AEPD is rather limited.

Metabolism and excretion

According to the chemical structure of AEPD, it can be assumed that AEPD is not metabolised in-vivo. Modelling of potential metabolites via OECD QSAR toolbox v.2.0 (2010) confirms this assumption. No relevant metabolites were generated by the liver metabolism simulator, by the skin metabolism simulator or by the microbial metabolism simulator. Based on this information, it seems to be very unlikely that AEPD will be metabolised by cytochrome P450 enzymes in-vivo.

Moreover studies on genetic toxicity in vitro (Ames test, gene mutation in mammalian cells in-vitro, chromosome aberration in-vitro) were all negative, indicating that there is no evidence of reactivity of AEPD under in-vitro test conditions. With respect to skin sensitisation data, there was no evidence that the test substance exhibits direct protein reactivity which would cause skin sensitisation. Since no interactions with proteins were determined and no relevant metabolites were generated via QSAR modelling, reactivity of the test substance is considered rather unlikely under in-vitro and in-vivo conditions.

Since AEPD is a polar substance, highly water soluble and has a molecular weight below 500, the substance is mainly excreted via the kidneys in a non-metabolised form.

The hypothesis that AEPD is not metabolised in vivo and is readily excreted predominantly via urine is confirmed by the toxicokinetic study of Saghir et al. (2008). This study was conducted to determine absorption, distribution, metabolism and excretion of the biocide Bioban™ CS-1246 following oral and dermal exposure in rats. Orally administered Bioban™ CS-1246 was rapidly absorbed and readily eliminated predominantly via urine within 144-168 h after dosing. Furthermore the biocide was completely metabolised, detecting AEPD as the only metabolite above 5% of the administered dose in all urine and faeces samples and analysed from all dose groups. Compared to the oral administration, dermal absorption was low and slow (43% of the applied dose remained unabsorbed) likely due to cornified layer of cells on the skin surface that work as a barrier. In compliance with limited absorption of the applied dose, elimination was also low. AEPD was detected as the only metabolite above 5% of the dermally applied dose in all urine and faeces samples. Based on the results of this study, AEPD is not expected to accumulate upon exposure.

Taking into account all available data, the biological properties of AEPD are mainly governed by its intrinsic alkalinity. AEPD possesses a low acute toxicity and is expected to have only a low potential to accumulate in biological systems.

 

References:

Potts, R. and Guy, R. (1992) Predicting skin permeability. Pharm. Res. 9(5): 663-669

Kroes, R. et al. (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45, 2533–2562

Mostert, V. and Goergens, A. (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for a refined route-to-route extrapolation. Society of Toxicology, Annual Meeting, ISSN 1096-6080 (http://www.toxicology.org/AI/PUB/Toxicologist11.pdf), 120(2): 107

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