Iso(C10-C14)alkyl (3,5-di-tert-butyl-4-hydroxyphenyl)methylthioacetate

Endpoint summary

Additional information

Assessment of the Toxicokinetic Behavior

The test substance is a yellowish viscous liquid with a density of 979.3 kg/m³ at 20°C, a boiling point of 396°C at 1013 hPa and a molecular weight of 492 g/mol. The test article has a vapor pressure of 0.000036 Pa at 20°C and is characterized by very low water solubility (< 0.08 mg/l at 20°C) and good solubility in fat (>100 g/100 g of fat). The log Pow was determined to be 11.6. No studies are available investigating the toxicokinetic properties of the test substance. The toxicokinetic behavior is therefore assessed based on physic-chemical properties and on available toxicity studies.

Absorption

The molecular weight of the test substance is below 500 g/mol and therefore absorption is favored. The lipophilic character and the high log Pow do not suggest absorption by passive diffusion, however highly lipophilic compounds can be taken up by micellular solubilization, particularly those that are poorly soluble in water, which is the case for test substance. It is therefore concluded that the test substance might be absorbed in the gastro-intestinal tract after oral administration and distributed to target organs by the systemic blood circulation thereafter. This is confirmed by the appearance of toxicity up to lethal effects after oral exposure. In subacute toxicity studies in rodents, liver was identified as target organ. The liver effects (increased organ weight, centrilobular enlargement of hepatocytes and induction of cytochrome P450 and lauric acid 11- and 12-hydroxylase activity) characterized the test article as a phenobarbitone-like inducer and peroxisome proliferator. This is supported by ultrastructural investigations demonstrating an increase in number and size of peroxisomes and a moderate proliferation of smooth endoplasmic reticulum membranes. The effects in the liver are considered to be an adaptive response of the test article acting as an inducer of hepatic drug metabolizing enzymes.

Absorption via skin is expected to be very low, since molecular weight and its high log Pow impede skin permeability. This is supported by the absence of systemic toxicity in the acute dermal study. Inhalative exposure to the test substance is of no relevance due to its low vapor pressure.

Metabolism

Metabolism of the test article by the action of esterases and carboxy esterases in the intestinal cells, plasma and hepatocytes will probably affect the ester moiety and lead to the formation of the free acid and 1-tridecanol. The latter is expected to undergo ω-oxidation in the microsomes and consequently to be degraded via acetyl-CoA and the Krebs cycle. A significantly minor amount of ester cleavage is already possible under acidic conditions of the stomach. However, acidic ester hydrolysis is assumed to occur rather slowly. Contrarily, esterases act quickly and efficiently. In consequence, the amount of free acid and long-chain alcohol generated in the stomach significantly depends on the rate of gastro-intestinal passage. Metabolism at the phenolic hydroxyl-group is unlikely to occur based on steric hindrance by the tertiary butyl groups in ortho position.

Excretion

As the symptoms in the subacute toxicity studies were mostly reversible within the recovery period of two weeks, the test substance is assumed to be eliminated efficiently. This is supported by the results of ADE studies in rats and miniature pigs with the structure-related, C¹⁴-radiolabeled S-(3,5-di-tert-butyl-4-hydroxybenzyl)-thioglycolic-acid-2-ethyl-hexylester. A C¹⁴-radiolabel at the phenolic moiety facilitates the recovery of the parent compounds as well as of the toxicological most critical moiety of the substance - the free acid - after metabolic ester cleavage. It can be assumed that the long-chain alcohol 1-tridecanol is of low toxicological concern. An effective metabolic degradation and renal elimination associated with a neglectable accumulating potential is likely. C¹⁴-labeled S-(3,5-di-tert-butyl-4-hydroxybenzyl)-thioglycolic-acid-2-ethyl-hexylester is rapidly absorbed via the gastrointestinal tract, reaching maximum blood concentrations at 2-4 hours post administration. Radioactivity, reflecting the parental compound and its metabolically formed free acid, decreased markedly in blood within 48 hours after administration. Fecal excretion was identified as the main route of elimination. Within a 168 hours period, C¹⁴-labeled S-(3,5-di-tert-butyl-4-hydroxybenzyl)-thioglycolic-acid-2-ethyl-hexylester was eliminated entirely.