2,4,6-tris(dimethylaminomethyl)phenol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

Assessment based on physico chemical properties of the test material and on toxicological data. Experimental toxicokinetic studies were not performed.

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment based on physico chemical properties of the test material. Experimental toxicokinetic studies are not available.

Principles of method if other than guideline:

Assessment of toxicokinetics based on physico chemical data.

GLP compliance:

no

Reference 2

Endpoint:

basic toxicokinetics in vivo

Data waiving:

other justification

Justification for data waiving:

other:

Description of key information

There were no studies available in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of 2,4,6- (dimethylaminomethyl)phenol were investigated. An assessment of the kinetic behaviour was based on the physico-chemical properties of the compound.

Based on the molecular structure, molecular weight, water solubility, vapour pressure and octanol-water partition coefficient it can be expected that only oral absorption rates are significantly existent. The results from the acute and repeated oral toxicity dose studies confirm that the substance has moderate oral absorption rates. Based on a very low log Kow which indicates a low lipophilicity of the test item, significant dermal absorption is not expected. Due to the very low vapour pressure of the test item significant respiratory absorption via vapour is also not expected.

Additional information

The following remarks on the toxicokinetics of tris 2,4,6-(dimethylaminomethyl)phenol are based on physiochemical properties of the compound and on toxicological data. Experimental toxicokinetic studies were not performed.

The substance is a pale yellow liquid having a molecular weight of 265.4 g/mol. It has a vapour pressure of 0.075 Pa at 25°C (SafePharm Labs, 2003) and has a very high solubility in water of 850 g/L at 20°C (SafePharm Labs, 2003) under normal ambient conditions.

The partition coefficient octanol/water (log Kow) was determined to be – 0.66 (at 21.5°C) (SafePharm Labs 2003). This value is much lower than the screening threshold (log Kow > 4.5 ) which is described as borderline for lipophilicity of an organic substance in aquatic organisms (ECHA guidance R11). According to this guideline, for organic substances with a log Kow value below 4.5 it is assumed that the bioaccumulative criterion, i.e. a BCF value of 2000 (based on wet weight of the organism, which refers to fish in most cases), is not exceeded. Hence, it can be assumed that the substance has a low potential for bioaccumulation.

Oral and GI absorption: The substance is not hydrolyzed in water but has a very high water solubility because of the hydrogen bonds of the three amino groups (-NH2) and the phenol group. Because of the high pka value of the amino groups, the substance is assumed to be protonated in the GI tract leading to bad absorption. Therefore, the substance is assumed to be excreted very fast via urine. The acute oral toxicity study also confirms a low absorption of the substance as the LD50 =2169 mg/kg is very high. However, local effects in the GI tract occur such as corrosion, which is caused by the high corrosiveness of the substance.

However, some oral absorption could not be totally excluded based on the results of the repeated dose toxicity study (LPT 2017). Based on this 90 day study according to OECD 408 with rats exposed to 15, 50 and 150 mg/kg bw/day, the LOAEL was determined to be 50 mg/kg/day. At this dose level decreased food and drinking water consumption, changes in biochemical parameters and organ weights and histopathological effects occurred.

Dermal absorption: Dermal absorption of the substance is anticipated to be very low, due to the higher molecular weight of the substance and the very low log kow value of – 0.66 indicating a low lipophilicity. The test substance showed clear dermal irritation and corrosion in an acute dermal irritation/corrosion study (SafePharm labs 2003), but no signs of systemic toxicity were observed. The dermal LD50 value was higher than 2000 mg/kg bw.

Inhalation absorption: As already explained above the test substance has a low vapour pressure of 0.075 Pa at 25°C (standard atmosphere is defined as 101325 Pa). Therefore, under normal handling an exposure via air is not expected. However, if aerosol is inhaled, the test substance will react immediately with cells in the upper respiratory tract such as nose and/or mouth due to its corrosive properties and high water solubility.

Metabolism: No indications and data on metabolism are available.

Distribution:Due to its physico chemical properties (high pka value, high molecular weight and low log kow) the substance is assumed to be only badly absorbed and not distributed in the body.

Excretion:No data are available regarding the excretion of absorbed 2,4,6-(dimethylaminomethyl)phenol. Based on the high water solubility, the substance is assumed to be excreted very fast via urine.

Accumulative potential: The substance is assumed to have no accumulation potential because of the high water solubility and the very low log kow value of – 0.66.

Mutagenicity: Based on the results of several mammalian in vitro genotoxicity tests (Ames (SafePharm 2003), Chromosome Aberration (SafePharm 2004), Gene mutation (Harlan 2011); all performed with and without metabolic activation) it is concluded that DNA-reactive metabolites of the test item will not be generated in mammals in the course of hepatic biotransformation.