Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Taking into account all available data, the biological properties of DMAMP are mainly governed by its intrinsic alkalinity. DMAMP possesses a low acute toxicity and is not expected to accumulate in biological systems.

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-(dimethylamino)-2-methylpropan-1-ol (DMAMP) were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of DMAMP according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2009)”.

DMAMP (117.19 g/mol) is a colourless to yellow liquid at room temperature with an ammoniacal odor. However, the physical state of DMAMP depends on the ambient temperature. Above its melting point of approximately 13 °C, DMAMP is a liquid and a solid below (Harlan, 2011). DMAMP is produced as practically anhydrous liquid, whereas the commercial product is an aqueous formulation of approximately 80% DMAMP. As the anhydrous form is a liquid, the aqueous solutions are obviously liquids at room temperature at any dilution. In general, the solid state of DMAMP will not be available during manufacturing or handling.

DMAMP is highly soluble in water (1000 g/L) and has a vapour pressure of 721 Pa at 25 °C (Harlan, 2011). The relatively low partition coefficient (log Kow) of 0.09 indicates that DMAMP is not expected to accumulate in biological systems (Angus, 1996).

 

Absorption and distribution

An acute oral toxicity study was performed similar to OECD 401 (Parekh, 1982). 10 male and female rats per dose level were administered 950, 1500, 1900, 2400 and 3000 mg/kg bw of a 72% solution of DMAMP by gavage. The mortality was 1, 1, 7, 10 and 10 for the males and 0, 4, 7, 9 and 10 for the females, respectively. Lethargy, ataxia and other signs of severe discomfort were observed in the low dosed females and in males and females in all other dose groups from 4 h after dosing. The effects lasted up to 24 h in the lowest dose group and until day 4-5 or death in the remaining dose groups. In the rats that died, severe stomach- and intestinal hemorrhage was noted, indicating a local irritating effect of the test substance due to the alkaline pH (12.5). The calculated LD50 for females was 1656 mg/kg bw, for males 1767 mg/kg bw, and the combined LD50 was 1712 mg/kg bw.

The findings in the acute oral toxicity study support the hypothesis that the main cause of acute toxicity was most probably local irritation at the site of contact due to the highly alkaline test substance. With respect to the dose administered and the effects observed, systemic bioavailability of the test substance is considered to play only a minor role after single oral administration of DMAMP. An oral repeated dose toxicity study performed in rats according to OECD 408 showed very slight to slight hyperplasia with inflammation of the limiting ridge in males and females in the highest dose group of 1000 mg/kg bw/day (Wasil, 2012). Again, the damage to the limiting ridge is most likely caused by local irritation of the test substance. In addition, at1000 mg/kg bw/day, treatment-related effects were found in the liver of females and in the kidney of males, indicating that DMAMP is systemically bioavailable after repeated oral administration. Whether the effects observed are reversible has not been tested. No toxicologically relevant changes in hematology parameters and no treatment-related effects on body weight, body weight gain and food consumption were found.

No data on acute inhalation toxicity are available. As the physical state of DMAMP is liquid during manufacturing or handling, inhalation exposure from the solid can be excluded. However, as the vapour pressure is 721 Pa (at 25 °C), there is a potential for inhalation exposure. Industrial and professional workers may be exposed via spray applications containing ≤ 1% DMAMP, which means that the potential for acute toxicity via the inhalation route is considered to be negligible. Consumers will not be exposed to DMAMP via spraying applications.

In an acute dermal toxicity study performed similarly to OECD 402, rabbits were exposed to an alkaline 72% solution (pH 12.5) of DMAMP (Parekh, 1982). The abdominal skin area of rabbits was treated with 2000 mg/kg bw of the test substance under occlusive conditions. After 24 h, the skin area was cleaned and the animals were observed for 14 days following administration. No mortality was observed and no clinical signs were noted. The internal organs in all the rabbits were grossly normal, except the small intestines in some of the animals showed adhesions. At the end of the 24 h exposure, the treated skin areas of all rabbits were black in colour. After one week, the same skin areas were hard and showed eschar formation. The LD50 is considered to be > 2000 mg/kg bw. With respect to the intrinsic alkalinity of DMAMP it was predicted that the primary effect after dermal exposure is local skin irritation/corrosion at the site of contact. Furthermore, it can be assumed that the dermal bioavailability of DMAMP is rather limited due to the high water solubility, the very low lipophilicity and the molecule size. A QSAR based modelling published by Potts and Guy (1992), taking into account molecular weight and log Kow, estimated a dermal permeability constant Kp of 4.03E-04 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 403 µg/cm²/h DMAMP. Usually, this value is considered as indicator for a dermal absorption of 80% (Mostert and Goergens, 2011). For neat DMAMP (i.e. basic solution), a dermal absorption of 80% was calculated using QSAR and the available physico-chemical properties. Based on practical experience, the dermal absorption of 80% has to be regarded as a worst case scenario: DMAMP is usually used in aqueous formulations where the pH will be closer to neutral. As a consequence DMAMP will predominantly be present in an ionised form which will not easily penetrate the skin. In addition, as no systemic toxicity was found in the acute dermal toxicity study up to 2000 mg/kg bw, it is expected that systemic bioavailability after dermal administration of DMAMP is rather limited.

Taking into consideration all available data on absorption via the oral, inhalation or dermal exposure route, the biological properties of DMAMP are mainly governed by its intrinsic alkalinity. But account needs to be taken of the fact that DMAMP is systemically bioavailable after repeated oral administration. No experimental data are available on distribution after oral, inhalation or dermal administration of DMAMP.

 

Metabolism and excretion

From the chemical structure of DMAMP, it can be deduced that DMAMP is not metabolized into chemically reactive compounds under in-vivo conditions. By calculating potential metabolites via OECD QSAR toolbox v.2.0 (2010), this assumption is confirmed. Relevant metabolites were generated neither by the liver metabolism simulator nor by the skin metabolism simulator nor by the microbial metabolism simulator. Based on this information, it seems to be very unlikely that DMAMP 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 the generation of chemically reactive metabolites of DMAMP under in-vitro test conditions. With respect to skin sensitisation data, no interactions with skin proteins were determined via QSAR modelling. Therefore, reactivity of the test substance under in-vitro test conditions is considered rather unlikely. This supports the hypothesis that metabolism of DMAMP into chemically reactive compounds is not to be expected.

Since DMAMP is a polar substance which is highly water soluble and has a molecular weight below 500, elimination of the fraction which is systemically bioavailable will mainly occur by the kidneys. In the urinalysis performed in the developmental toxicity screening study of Raspoulpour and Andrus (2011), DMAMP was detected in the urine of female rats, indicating that DMAMP is systemically bioavailable. The urine was collected following the first dose at 100 and at 250 mg/kg/day DMAMP. Levels of DMAMP measured in the urine were proportional to the administered dose: Following the dose at 100 mg/kg/day, 1178 ± 398 µg DMAMP/g urine was detected and following the dose at 250 mg/kg/day, 2434 ± 528 µg DMAMP/g urine was found. The fraction of DMAMP which is not absorbed via the gastrointestinal tract will be excreted via the feces.

Taking into account all available data, the biological properties of DMAMP are mainly governed by its intrinsic alkalinity. DMAMP possesses a low acute toxicity and is not expected 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