Potassium N,N-dimethylglycinate

Endpoint summary

Description of key information

Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient (Pow) absorption via oral route is likely to occur. Dermal uptake will be limited due to the hydrophilic character of the test substance and the barrier function of the stratum corneum against ions. Based on the low vapour pressure of the compound, absorption via inhalation route is also unlikely to happen. Once absorbed, distribution in fatty tissues and bioaccumulation is unlikely. Due to the high water solubility, metabolic conversation is unlikely and excretion via urine is assumed to be the main excretion pathway.

Additional information

General background and toxicological profile of Glycine, N,N-dimethyl-, potassium salt
Glycine, N,N-dimethyl-, potassium salt is a white salt with the formula C4H8KNO2.
The acute oral LD50 of the test substance (45% solution) after single oral administration to Wistar rats is > 5000 mg/kg bw/day (BASF 1979, 78/498). The observed LD50 after dermal application on the clipped skin of Wistar rats is > 2000 mg/kg bw/day and no macroscopic pathological abnormalities were noted (BASF 2015, 11A0456/01X069).

The results of two skin irritation studies (BASF 1979, 78/498) showed that the test substance is not irritating to the intact skin of Vienna White rabbits after 4 h. With the Draize test, the substance is slightly irritating to the intact skin of Vienna White rabbits. The results of an eye irritation study (BASF 1979, 78/498) demonstrated, that the test compound needs to be considered as irritating to the eye of Vienne White rabbits and was classified as eye damaging, cat.1.

Skin sensitization was not observed in an LLNA test in mice (OECD 429; BASF 2015, 58V0456/01X070).
In a repeated-dose oral toxicity study in rats, following OECD 422, the test substance was administered daily as solutions to groups of 20 Wistar rats (10/sex) via drinking water. Under the conditions of this test, the oral administration via drinking water of the test substance to rats revealed no signs of general systemic toxicity in male and female parental animals up to a concentration of 12000 ppm (731 mg/kg bw/day in males and 960 mg/kg bw/day in females). Further, no signs of reproductive or developmental toxicity were observed. Thus, the NOAEL for general systemic toxicity and reproductive performance and fertility was 12000 ppm in male and female parental animals (731 mg/kg bw/day in males and 960 mg/kg bw/day in females). The NOAEL for developmental toxicity in the F1 progeny was also 12000 ppm.
The genetic toxicity of the test substance was investigated in a bacterial reverse mutation assay (OECD 471; BASF 2015, 40M0456/01M019), HPRT assay (OECD 476; BASF 2015, 50M0456/01M022) and a Micronucleus assay (OECD 487; BASF 2016, 33M0456/01M020). All tests were considered negative with and without metabolic activation and no genetic toxicity of the test substance was observed.

Toxicokinetic assessment of Glycine, N,N-dimethyl-, potassium salt 

The test substance is a white powder at room temperature with a molecular weight of 141.2101 g/mol and a density of 1.374 g/cm³ at 20 °C. The melting point of the substance is in the range between 193 and 232 °C and a vapour pressure of < 1*10^-6 hPa at 20 °C, 25 °C and 50 °C was determined. The substance is easily soluble in water as indicated by the measured water solubility value of 910 g/L at 20 °C. The experimentally determined partition coefficient between octanol and water (log Pow) value of -2.91 is very low.

Absorption 

Oral route 

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgement of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow need to be considered. According to ECHA Guidance Document R.7c, the smaller the molecule the more easily it gets through the walls of the gastrointestinal tract (GI). Molecular weights below 500, like the molecular weight of the test substance, are favourable for absorption. In addition, the very low log Pow indicates that the test substance is very hydrophilic and the high water solubility facilitates the absorption of such a substance due to its ability to dissolve into the GI fluids and hence make contact with the mucosal surface. In addition, the very low log Pow indicates that the substance is very hydrophilic and the high water solubility facilitates the absorption of such a substance due to its ability to dissolve into the GI fluids and hence make contact with the mucosal surface. Thus, passive diffusion of the substance is possible due to its hydrophilic nature, but is limited by the rate at which the substance partitions out of the gastrointestinal fluid. However, substances with small molecular weights (less than 200) may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. With regard to the toxicological data, no signs of systemic toxicity were observed in the acute oral acute toxicity study (BASF 1979, 78/498) as well as in the repeated-dose study (BASF 2016, 88R0456/01C029).

Inhalation route 

The test substance has a low volatility potential due to its very low vapour pressure of 0.000001 hPa. Thus, inhalation as a vapour is very unlikely. However, absorption via inhalation as dust might be possible. Due to the high water solubility, dusts would readily dissolve into the mucus lining the respiratory tract. Such substances may be transported out of the deposition region with the mucus and swallowed or may pass the respiratory ephithelium via aqueous membrane pores. Thus, uptake of high amounts directly across the respiratory tract epithelium is not expected. No information from acute or repeated dose toxicity studies is available, which could provide information about the systemic distribution of the test substance after inhalation.

Dermal route 

To assess the potential of a substance to cross the skin, basic physicochemical properties of the substance, i.e. molecular weight, water solubility and lipophilicity (log Pow), should be taken into account. The test substance has a very low molecular weight which favours the dermal uptake. Nevertheless, dermal uptake of the substance is expected to be low due to its hydrophilic properties and the barrier function of the stratum corneum against ions. With a water solubility above 10,000 mg/L and a log Pow value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. This assumption is supported by the toxicological data achieved by a skin sensitization study (BASF 2015, 58V0456/01X070) and two acute dermal toxicity studies (BASF 1979, 78/498). The studies did not reveal that relevant amounts were absorbed into the systemic circulation as no systemic effects were observed. Based on the findings on the intact skin, the test substance is not considered as a skin irritant with respect to edema or erythema but is considered as a slightly skin irritant only due to skin scales formation (not relevant for classification purposes). The latter does not enhance skin penetration.

Distribution 

As mentioned above, the physicochemical properties and toxicological data revealed that the test substance can become systemically available following oral exposure. Once absorbed, the distribution of the test substance via blood stream can be assumed. The small molecular weight of the substance supports a wide distribution. Due to its high water solubility and very low Pow value distribution in fatty tissues is unlikely. In general, the transport efficiency to body tissues is limited by the rate at which the test substances cross cell membranes. For instance, access of highly water soluble substances to the central nervous system (CNS) or testes is likely to be restricted by the blood-brain and blood-testes barriers (Rozman and Klaasen, 1996). 

Metabolism 

Biotransformation of a substance aimed to increase the hydrophilicity of lipophilic substances by Phase I (functionalization) and Phase II (conjugation) enzymes. Due to the high water solubility of the test substance, metabolic conversion is unlikely. In addition, based on the results of the Ames test (BASF 2015, 40M0456/01M019), Chromosome Aberration test (BASF 2016, 33M0456/01M020) and HPRT test (BASF 2015, 50M0456/01M022) it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the parent compound showed no higher toxicity compared to the metabolic activated substance.

Excretion 

Excretion can occur via the urine especially for small (below 300 g/mol) and water-soluble substance and/or via biliary excretion predominantly for larger molecules. Based on the high water solubility and the low molecular weight of the test substance, excretion might occur primarily via urine.

Summary

Based on the physicochemical properties particularly molecular weight, water solubility and log Pow, absorption via the gastrointestinal tract is likely. Uptake of relevant amounts following dermal exposure most likely does not occur due to its very high water solubility and its very low log Pow. Based on its low vapour pressure it is unlikely that the test substance will become systemically available after inhalation of vapour. After absorption, the test substance will circulate within the blood stream. Bioaccumulation is not to be expected based on the high water solubility and low partitioning coefficient. Due to the high water solubility, metabolic conversation is unlikely and excretion via urine is assumed to be the main excretion pathway.