1-(dimethylamino)propan-2-ol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Since only one toxicokinetic study is available for dimethylisopropanolamine focusing mainly on the excretion of the test substance, the following assessment additionally takes available data on physicochemical properties and results from other toxicological studies into account.

 

Physical-chemical properties

Dimethylisopropanolamine (MW: 103.1628 g/mol) is a liquid with a melting point of -85 °C, a measured boiling point of 125.6°C, a measured vapour pressure of 17.46 hPa at 26.5°C, and a dissociation constant (pKa) of 9.45 at 25°C. Its relative density is 0.85 g/cm³at 20°C The calculated octanol-water partition coefficient (log Pow) is -0.52 at 25°C, and the substance is miscible in water. According to structural properties, enzymatic hydrolysis is not expected.

 

Adsorption

Gastrointestinal absorption:

The small molecular weight of < 500 g/mol, and the moderate log Kow of -0.52 make the test item favourable for absorption in the GI tract. In the gastrointestinal tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. In line with this, single and repeated dosing via the oral route resulted in adverse effects in rats. In an acute oral toxicity study no mortality occurred up to 680 mg/kg bw, but 10/20, 10/20, 6/10 and 9/10 animals died at 1360, 1700, 2125 and 2720 mg/kg bw within 1-3 days (BASF, 1964). On the day of administration apathy, staggering and dyspnea were observed in the treated animals. On the following days, the animals showed calm behavior, fluffy fur and crusted eyes. The surviving animals were without findings within 4-6 days. Haemorrhagic gastroenteritis in the dead animals, organs of the surviving animals without findings. Necropsy revealed haemorrhagic gastroenteritis in the deceased animals. Organs of the surviving animals were without findings. In an OECD TG 422 study (BASF, 2019), the oral administration of the test substance by gavage to rats induced signs of toxicity at a dose level of 375 mg/kg bw/d in terms of clinical findings (respiratory sounds), body weight loss and food consumption. At lower doses, no treatment-related, adverse effects were observed. Of note, the substance is classified for Skin Corrosion Cat. 1B (H314: Causes severe skin burns and eye damage). Thus, the adverse effects observed are probably also attributable to local rather than systemic effects. In line with this, rather unspecific clinical effects and body weight loss occurred at 700 mg/kg in the preceding range-finding study. Due to the severity of the observed effects, all animals of this dose group had to be sacrificed on study day 2. Deceased animals revealed foci in the glandular stomach and thickening of the dudenum wall, suggesting local effects of the test substance. No such effects were seen at lower doses over the course of the whole study period, indicating a concentration dependency rather than dose dependency. Due to the nature of the adverse effects observed in the acute and repeated-dose toxicity tests, it remains unclear whether the substance is systemically available after oral administration. However, urinary excretion products derived from [14C]-radiolabelled N,N-dimethylaminoisopropanol were determined following single oral administration to rhesus monkeys, suggesting a gastrointestinal absorption (Streeter and Pfadenhauer, 1984).

Respiratory absorption:

Due to moderate vapour pressure of the test substance (11.7 hPa at 20°C, 25.8 hPa at 25°C, 60.2 hPa at 50°C), inhalation exposure to vapors has to be considered. The moderate Log Kow value between -1 and 4 (-0.52 at 25°C) is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, vapours of very hydrophilic substances like dimethylisopropanolamine may be retained within the mucus. Since dimethylisopropanolamine is classified for corrosivity, studies regarding inhalation toxicity do not have to be conducted. However, some limited information regarding acute inhalation toxicity is available. In an inhalation-risk test, exposure to 72.2 mg/L for 3 minutes did not cause mortality, after exposure to 55 mg/L for 10 or 30 minutes 1/12 or 6/6 animals died, respectively (BASF, 1964). An LC50 has not been determined. The animals showed attempts to escape, severe irritation of the mucous membrane, dyspnea and blood incrusted noses. Necropsy revealed no organ-related findings, except for greyish-brown incrustation in the nasal area of deceased animals. The adverse effects observed are probably also attributable to local effects due to corrosivity rather than systemic effects following respiratory absorption. Since toxicokinetic data indicate the potential for absorption following ingestion in rhesus monkeys (Streeter and Pfadenhauer, 1984) it is likely the substance will also be absorbed if it is inhaled.

Dermal absorption:

Liquids and substances in solution are taken up more readily than dry particulates. Also, the small molecular weight of 103 g/mol favours dermal uptake. However, absorption of volatile liquids across the skin may be limited by the rate at which the liquid evaporates off the skin surface (Pryde and Payne, 1999). Moreover, due to the high water solubility and the log Kow value of <-1, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum, leading to low dermal uptake. However, since the substance is a skin corrosive, damage to the skin surface may enhance penetration. In an acute dermal toxicity test according to OECD guideline 402, 3 groups of rabbits (5/sex/dose) were treated with 500-2000 mg/kg bw dimethylisopropanolamine at a single intact skin site (clipped) for 24-hours and subsequently observed for a 14-day period (Pharmacon Research International, Inc., 1994). None of the animals died at 500 mg/kg bw, 5 of 10 animals died at 1000 mg/kg bw and 7 of 10 animals died at 2000 mg/kg bw. Decreased activity, chromodacryorrhea abnormal gait, abnormal stance, erythema, necrosis and brown nasal discharge were observed. Animals that died did not show clinical signs. Necropsy of the animals that died on study revealed distended and/or fluid-filled intestines and stomach. Necrosis of the skin at the application site was noted in all animals. No other visible lesions were observed in any of the animals at terminal necropsy. The LD50 was 1232 mg/kg bw. However, the adverse effects observed are probably also attributable to local effects due to corrosivity rather than systemic effects following dermal absorption.

Absorption rates:

No data on quantitative absorption are available. Therefore, for the DNEL derivation the default as reported in the REACH guidance will be used; an absorption of 50% is assumed for the oral and dermal route; and an absorption of 100% is assumed for the inhalation route. As dimethylisopropanolamine is a corrosive substance, risk management measures are applied to prevent dermal exposure.

Distribution and Accumulation

Since the test substance is a relatively small water-soluble molecule, it probably diffuses through aqueous channels and pores. Therefore, a distribution into different organs hast to be assumed. Due to the moderate log Kow of -0.52 and the high water solubility, the test substance is unlikely to accumulate in adipose tissue with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous.

 

Metabolism and Excretion

According to structural properties, enzymatic hydrolysis is not expected. Molecules with available functional groups, such as -OH tend to undergo Phase II conjugation reactions. Using the OECD toolbox vs.4.3.1, the in vivo Rat metabolism simulator provided 9 potential simulated metabolites, as well as 1 simulated skin metabolite. Studies assessing genotoxicity (Ames test; BASF, 1999; HPRT test, BASF, 2012; MNT, BASF, 2013) were negative, i.e. there is no indication of a reactivity of the test substance or its metabolites with macromolecules under the chosen test conditions. Based on the molecular weight of the parent compound and its water solubility, it is conjectured that the test substance would probably primarily undergo a renal elimination. In line with the assumptions made based on structural properties, toxicokinetic data indicate the that the substance is mainly excreted via urine following oral or i.v. administration of [14C]-radiolabelled N,N-dimethylaminoisopropanol to rhesus monkeys (Streeter and Pfadenhauer, 1984). Moreover, this study identified dimethylaminoisopropanol-N-oxide as an urinary metabolite of dimethylisopropanolamine. This Metabolite accounted for 17 - 18% of the administrated radioactivity in either the i.v. or orally dosed animals. 48% (i.v.) and 55% (oral) of the total radioactivity were assigned to the parent compound. Thus, the proportions of dimethylaminoisopropanol-N-oxide and dimethylaminoisopropanol appeared to be unaffected by route of administration, with the parent compound dominating in both cases.