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

Endpoint summary

Additional information

No ADME studies are available for the test article; therefore, the toxicokinetic properties are assessed considering the physico-chemical parameters and the available toxicity data of the test article. In addition, the toxicokinetic data obtained with the read across substance are taken into consideration. For read across justification see chapter 13.

The test substance (molecular weight: 642.94 g/mol) is a white crystalline powder with a log P_ow = 10 (calculated, EPI Suite), a water solubility < 1 mg/L, and a vapor pressure of 1.33E-9 Pa at 25°C.

Oral Absorption

In an acute oral toxicity study in rats no mortality was observed at a dose level of 5000 mg/kg body weight. Clinical signs reported were dyspnoea, exophthalmus, ruffled fur and curved body position, all commonly observed in acute toxicity tests. No strong indications for systemic availability could be derived. This result together with the high log Pow value suggests a poor absorption. However, in a 90-day oral toxicity study in rats increased liver weights were reported, suggesting a functional adaptation of the liver to increased systemic load indicating absorption and at least partial systemic availability of the test substance. In view of the absence of relevant findings, it can be assumed that the test substance and its metabolites are rapidly excreted upon absorption and liver passage.

In toxicokinetic studies performed with the read across candidate, it could be shown that the read across substance is rapidly absorbed in considerable amounts (50%) after ingestion and undergoes enzymatic ester hydrolysis in the liver. Absorption was rapid since the maximal blood/plasma values were reached one hour after administration. Radioactivity from plasma and blood was eliminated with half-lives ranging from 2.9 hours to 8.6 hours. Elimination with approximately equal ratio in urine and feces was basically complete within 72h. There is no indication of bioaccumulation of the substance.

In conclusion, based on the toxicity data of the test compound and taking the data from a read across substance into account, absorption of the test material through the GI tract is expected followed by rapid elimination by feces and urine.

Dermal Absorption

In a guinea pig maximization assay, no indications of systemic availability after dermal application were detected. Furthermore, dermal uptake of chemicals with a molecular weight > 500 is not favored (ECHA GD 7c, 2008). In conclusion, based on the physic-chemical properties, a dermal uptake of the test substance is expected to be low.

This is supported by the findings in a dermal absorption study performed with the structural analogue in miniature pigs. After dermal application of radiolabelled material, presence of urinary metabolites indicated that low amounts (less than 1%) penetrate the skin.

To summarize, based on the physico-chemical properties and the read across data, dermal absorption of the test article is expected to be low.

Inhalative Absorption

No reliable inhalation studies are available. Based on the low vapor pressure exposure to vapors can be excluded. Dust particles that are inhaled are expected to be poorly absorbed based on the low water solubility and removed by clearing mechanisms. The compound may be taken up by micellular solubilisation, a mechanism of importance for highly lipophilic compounds (log P > 4), particularly those that are poorly soluble in water (1 mg/l or less) and would otherwise be poorly absorbed (ECHA GD 7c, 2008).

Metabolism

Hydrolysis studies were performed in vivo and in vitro with the read across substance, a diester compound. It could be shown that this compound was readily hydrolyzed to the corresponding carboxylic acid at the near physiological pH of 7.4 with hydrolysis half-times of 26.2 and 14.0 min with a test concentration of 200 µM by 0.5 and 1% rat serum, respectively. This rapid hydrolysis was confirmed in rats. The test animals absorbed the read across substance rather rapidly as judged from the maximum of radioactivity in blood 1 hour after treatment. At any sampling time, starting as early as 15 min after the administration of the test read across compound, the carboxylic acid was the absolutely dominating metabolite in blood, whereas the parent compound constituted a minor component only. Conjugates of the metabolite are eliminated with approximately equal ratio in urine and feces and elimination is basically complete within 72h. Since the test article is also a diester with comparable structure, equivalent hydrolysis to the corresponding carboxylic acid in the liver is expected.

Excretion

Since the test substance has a molecular weight larger than 500 g/mol and a low solubility in water, excretion via the feces is suggested (ECHA GD 7c, 2008). However, based on the read across data, rapid hydrolysis in the liver is expected, resulting in the smaller and more soluble corresponding carboxylic acid. Therefore, excretion is expected to occur both via the feces and the urine.