p-tert-butylstyrene

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

The toxicokinetics information on the test substance has been compiled on the basis of its physico-chemical properties and by means of read-across to the close structural analogue, vinyl toluene.

Absorption

Oral

The test substance has a molecular weight below 500 (160.26), moderate water solubility (5 mg/L) and a log Pow of 4.44. These characteristics favour oral absorption via the gastro-intestinal tract, possibly via passive diffusion. Uptake through this route is confirmed in oral toxicity testing where clinical signs indicative of systemic effects were noted.

Dermal

Dermal absorption of the test substance is likely to be limited due to its volatility (the liquid can evaporate off the skin surface). In testing conducted with the closely-related substance styrene (CAS No. 202-851-5; EC No. 100-42-5), dermal absorption of the liquid was approximately 2% of the applied dose in anin vitrostudy using human skin samples (Gedik and Roper, 2003; cited in the REACH registration of styrene). In human volunteers exposed by placing one hand in liquid styrene for 10–30 min, absorption was low, averaging 1μg/cm2/min (Berodeet al., 1985). Also, dermal uptake of styrene vapour appears to make only a small contribution (5% or less) to the total body burden arising from combined inhalation and dermal exposure to the vapour (Wieczorek, 1985; Riihimäki and Pfäffli, 1978; Limassetet al., 1999).

Based on the above information, a conservative value of 10% dermal absorption was therefore taken forward for the risk assessment of p-tert-butylstyrene.

Inhalation

The test substance is volatile, so that exposure via inhalation is likely. As for the oral route, the molecular weight, water solubility and log Pow are in a range that favours direct absorption through the respiratory tract epithelium via passive diffusion.

Based on the above information, oral, dermal and inhalation uptake rates of 100, 50 and 100% respectively are assumed for risk assessment purposes.

Distribution

No information could be identified on the distribution of the test substance in the organism once taken up systemically.

Metabolism and excretion

A study was conducted to determine the metabolism of the read-across substance, vinyl toluene, in rats by investigating urinary metabolites after injection of different doses. Male Wistar rats received the test substance by single intraperitoneal injection in three different experiments. In the first, the test substance dissolved in olive oil was administered at 50, 250, 500 and 1000 mg/kg bw. Four rats were sacrificed after 12 h at each dose level and three rats at the dose levels of 50, 250 or 500 mg/kg bw after 23 h. In the second experiment, rats were given the test substance (500 mg/kg bw in olive oil), 1-phenylimidazole (50 mg/kg bw in DMSO) or both. The control rats received olive oil or DMSO alone. 1-Phenylimidazole and DMSO were administered 1.5 h before the test substance. Four rats of each group were sacrificed 12 h after injection of the test substance and 3 in each group after 23 h. In the third experiment, rats were exposed to PCBs (500 mg/kg bw in olive oil), test substance (500 mg/kg bw in olive oil) or both Controls received olive oil only. The dose of PCB was given 5 d before the test substance. Three animals in each group were sacrificed 23 h after injection of the test substance. Urine was collected during the exposure from all rats in all groups. The urinary metabolites analysed were: thioesters, p-methylmandelic acid, p-methylphenylglyoxylic acid, the glycine conjugates of p-methylbenzoic acid, p-methylphenylacetic acid and p-vinylbenzoic acid. The role of cytochrome P-450 in the formation of the metabolites was studied by inhibiting its catalytic activity. The highest excretion rate was obtained with doses of 50, 250 and 500 mg/kg bw already within the first 6 h. However, the dose of 500 mg/kg bw did not increase the excretion rates of these metabolites compared to the dose of 250 mg/kg bw, suggesting that the metabolic pathways begin to be saturated with the amount of 250 mg/kg bw. At 50 mg/kg bw, 55% of the dose was detected as urinary metabolites within 23 h, mainly within the first 6 h. The amounts of the excreted metabolites expressed as % of injected dose (250 or 500 mg/kg bw) were lower than that caused by 50 mg/kg bw, and a noticeable amount of the total sums were excreted within 11–23 h, suggesting that the excretion was still continued with the doses of 250 and 500 mg/kg bw 23 h after injection. The excretion of all analyzed metabolites was prevented by the pre-treatment of the rats with 1-phenylimidazole, an inhibitor of cytochrome P-450 monooxygenases. This indicates that these metabolites were formed as catalyzed by cytochrome P-450. The structures of the analyzed metabolites suggest that the main reactive intermediate of the test substance is vinyltoluene-7,8-oxide. Furthermore, the amounts of the excreted metabolites showed that the main detoxification pathways of vinyltoluene-7,8-oxide were the conjugation with reduced glutathione and hydration to diols. Pre-treatment of the rats with PCBs increased the excretion rates of the metabolites. However, the PCB pre-treated rats excreted less thioethers (62%) compared to the rats treated only with the same amount of test substance, whereas the total sum of the other metabolites was about the same in these both groups. This result suggests that PCBs change the metabolism of the test substance to some other pathway which could be glucuronide conjugation because PCBs increased the activity of UDP-glucuronosyltransferase in a dose-dependent manner (Heinonen, 1984).

References

Berode M et al. 1985: Human exposure to styrene. VI. Percutaneous absorption in human volunteers. Int. Arch. Occup. Environ. Health, 55 :331–336.

Gedik L and Roper CS, 2003: Thein vitropercutaneous absorption of radiolabelled styrene in two test preparations through human skin. Unpublished report. Inveresk report number 20825. Inveresk Research, Tranent EH33 2NE, Scotland. Cited in the European Union Risk Assessment Report for Styrene (2008).

Heinonen THH 1984: Metabolism of vinyltoluene in the rat: effect of induction and inhibition of the cytochrome P-450 (publication), Biochem. Pharmacol. 33(10):1585-1593.

Limasset JCet al.1999: Estimation of the percutaneous absorption of styrene in an industrial situation. Int. Arch. Occup. Environ. Health. 72(1):46-51. Erratum in: Int. Arch. Occup. Environ. Health 72(7):489.

Riihimäki V and and Pfäffli P 1978:Percutaneous absorption of solvent vapors in man.Scand. J. Work Environ. Health 4(1):73-85.

Wieczorek H 1985: Evaluation of low exposure to styrene. II. Dermal absorption of styrene vapours in humans under experimental conditions. Int. Arch. Occup. Environ. Health. 57(1):71-5.