Hexamethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]

Endpoint summary

Description of key information

The test article is absorbed to some extent after oral application as shown by toxic and adaptive responses in animal studies. The physicochemical properties do not favour transdermal absorption. Considering the low vapor pressure and the particle size distribution no relevant amounts of the test substance are expected to be inhalable under normal use conditions. The substance is expected to be distributed and metabolised following excretion via the bile. According to the calculated BCF value, bioaccumulation is very unlikely for the test substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic analysis

The test substance is a white to pale yellow crystalline powder with a molecular weight of 638.92 g/mol. The water solubility is very low (< 1 mg/L). A log Pow of 11.74 and a BCF value of 9.564 L/kg were calculated. The test substance has a very low vapor pressure of 3.14E-11 hPa at 20 °C.

 

Absorption

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 value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 638.92 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is limited but possible (ECHA, 2014). The compound is highly lipophilic (log Pow = 11.74) and has a low water solubility. Therefore the absorption is limited by the extent to which such substances dissolve into the GI fluids and hence set in contact with the mucosal surface. The absorption can however be enhanced via micellular solubilization by bile salts. The possible gastrointestinal absorption is strengthened by the results achieved in several feeding studies with rats and Beagle dogs. The repeated dose tests showed general toxic effects and changes in the liver after oral administration, indicating bioavailability of the test substance.

 

Considering the low vapor pressure of the test substance and the resulting low volatility, exposure of the substance as vapor is very limited if handled at room temperature. Even if inhaled, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract and might be swallowed. These assumptions are further supported by the results of the acute inhalation study where no mortality was observed after a 4h-exposure to the maximum attainable concentration.

 

In general, substances with a molecular weight below 100 are favored for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 638.92 g/mol, the dermal uptake is expected to be low. Dermal penetration is further confined by the high lipophilicity of the compound. As the chemical consists of a particulate at room temperature, it has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin. The assumption that low or no dermal absorption occurs is supported by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, the test article did not cause any toxic effects. The LD50 was determined to be greater than 10000 mg/kg bw. A negative Buehler assay in guinea pigs additionally supports the assumption of low dermal absorption.

Distribution

Based on the physico chemical properties and the results achieved from the comprehensive toxicity testing, small amounts of the test substance can become systemically available. Once adsorbed, the substance will most likely be transported within the body via the blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility.

 

Metabolism

Absorbed amounts of test material may be transformed within the body by Phase I enzymes while undergoing functionalization reactions aiming to further increase the hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the absorbed chemical, the respective Phase I metabolites or to the OH groups of the parent molecule in order to ultimately facilitate excretion. The chemical is most likely not enzymatically activated (toxified) during metabolism. The assumption is supported by the cytotoxicity results of an Ames assay. The cytotoxicity of the test substance was not higher as compared to the metabolically activated test substance.

 

Excretion

Based on the chemicals characteristics, excretion via urine can be regarded as negligible for the parent compound. The high molecular weight and the low water solubility limit the urinary excretion drastically. Biliary excretion is assumed to be the major way of excretion. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.