4-(1,1,3,3-tetramethylbutyl)phenol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In a set of four consecutive studies (Hüls BT-94/0125, BT-95/0125.13-) toxicokinetic parameters of p-(1,1,3,3-tetramethylbuty1)-phenol (OCT) were determined in male Wistar rats.
Short description of key information on absorption rate: 
The dermal absorption of radioactive labelled Nonylphenol and two nonylphenol ethoxylates (NPE-4, NPE-9) was tested in an ex vivo isolated perfused porcine skin flap (IPPSF) assay and an in vitro porcine skin flow  through (PSFT) diffusion cell assay.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

1

Additional information

Blood concentration profiles obtained after single oral and intravenous application were used to assess the potential of p-(1,1,3,3 -tetramethylbuty1)-phenol (OCT) to bioaccumulate in rats. The peak blood concentration was about 1970 ng/ml blood after single intravenous (i.v.) application of 5 mg/kg bw. The blood level rapidly decreased within 30 minutes after application. OCT was not detectable in the blood samples 6 - 8 hours after application. Fitting the data of blood concentration-time curves resulted in an elimination half-life (t1/2) of 310 min.

After single administration by gavage of 50 mg/kg bw a maximal blood level of about 40 ng/ml was reached within 20 min. Within 4 - 6 hours after dosing, blood levels decreased to 3 – 7 ng/ml. After oral application of 200 mg/kg, the blood concentration-time profiles of individual animals showed a high variation. The blood profiles indicated the presence of two peak blood concentrations, i.e. at 45 - 120 and 240 - 480 min after dosing, respectively, suggesting enterohepatic circulation. OCT was not detectable in blood samples of several animals 32 hours after dosing, while other animals showed low OCT concentrations in the blood 48 hours after dosing. The oral bioavailability was found to be 2 % and 10 % for the 50 mg and 200 mg dose group, respectively. This low bioavailability might be due to incomplete resorption from the gastrointestinal tract due to the low solubility of OCT in aqueous media or due to a marked first pass effect in liver or intestinal tissue.

The large variations observed in blood at low OCT-concentrations following gavage administration suggest caution in the interpretation of the data. However, the increased bioavailability after application of higher doses may be explained by saturation of elimination processes, resulting in higher OCT blood concentrations over a prolonged period of time.

The half-life of OCT elimination after single intravenous injection was 310 min: Using this value, an elimination of more than 95 % of OCT within 24 hours after intravenous application of 5 mg/kg is calculated. This calculation in addition to the blood concentration-time curves observed after single gavage application provides an indication regarding the bioaccumulation potential of OCT: At doses which are in the range of occupational and/or environmental relevant levels, the exposure to OCT should not lead to bioaccumulation. However, doses which are orders of magnitudes higher, a bioaccumulation of OCT may be expected.

In addition to the single oral and i.v. application repeated oral gavage administrations of 50 and 200 mg OCT/kg bw was investigated. And additional group of rats received OCT via drinking water saturated with 8 mg OCT/l, corresponding to a mean daily dose of 800 pg/kg over a period of 28 days. In the oral gavage groups, OCT was detected in the blood as early as 10 min after administration, indicating rapid uptake from the gastrointestinal tract. In the 50 mg/kg and 200 mg/kg dose group maximal blood levels of about 50 – 70 ng/ml and 80 – 100 ng/ml blood were determined, respectively. These blood levels decreased during the 24 hours after administration, but OCT was still detected at low concentrations prior to the next application. However, the blood concentration-time profile at day 14 was similar to the profile obtained at day 1, indicating that repeated oral gavage administration did not lead to increased blood concentrations.

OCT was not detected in blood samples from animals which received OCT via drinking water.

The results obtained during the study with repeated administration of OCT to male Wistar rats confirmed the results and conclusions of the study with single administration, that OCT has a low potential for bioaccumulation in male rats.

The same setup was used to assess OCT concentrations in tissues, obtained at sacrifice from animals receiving repeated dose oral gavage of 50, 200 mg OCT/kg bw, and ~800 pg/kg bw via drinking water, respectively. In the 50 mg/kg oral gavage group, OCT was detected in fat and liver tissue in 3 of 5 animals, with an average concentration of 10 and 7 ng/g tissue respectively. OCT has not been detected in any other tissues analyzed. In the 200 mg/kg oral gavage group, OCT was found in all tissues analyzed, but not in testes. The highest concentration was found in fat tissue (about 1285 ng/g), followed by liver, kidney, and muscle tissues with average concentrations of 87, 71, or 43 ng/g tissue. Low concentrations of about 9 or 7 ng/g tissue were found in brain and lung tissue. In the drinking water group OCT was not detected in any tissue.

The glucuronidation and sulfation of OCT has been characterized with regard to V_max and K_m in vitro, using liver preparations from male Wistar rats. Glucuronidation and sulfation are generally regarded as important detoxification pathways for phenolic compounds. It was investigated whether OCT is also metabolized via these pathways. The results demonstrate that rat liver has a high capacity for detoxification of OCT via glucuronidation and sulfation.

In a complementary in vitro study Moffat et al. (2001) showed that glucuronidation eliminates the estrogen-like activity of OCT. It is likely, therefore, that the weak estrogen-like activity noted for OCT at high doses in rats reflects the saturation of glucuronide conjugation. At concentrations present in the environment this metabolic saturation is unlikely to occur, thus enabling glucuronidation of OCT removes the ability of these chemicals to mimic biological estrogens in humans. It is therefore concluded that at the expected exposure levels, the potential endocrine hazard posed by OCT to humans is likely to be negligible.

Upmeier et al. (1999) rerun part of the toxicokinetic studies conducted in male Wistar rats using female DA/Han rates. Compared to the previous data set the biological half-life of OCT was found to be consistently longer. The final (Gamma-phase) t1/2 upon i.v. administration of 5 mg/kg was 310 min (5.17 h) in male Wistar rats (Certa et al. 1996), but 36.1 hours in female DA/Han rats. This difference is supported by data obtained after oral administration. This would indicate not only gender but also strain differences. The data show peculiarities in the time-course of OCT blood levels after oral administration of OCT, which indicate extensive enterohepatic circulation of this compound.

Conclusion:

OCT does not bioaccumulate in rats when administered at low concentrations. The substance is rapidly eliminated by a conjugated system of glucuronidation and sulfation. At high concentrations there is a potential of bioaccumulation, predominantly in fat tissue. It is suggested that this is due to the saturation of the metabolic capacity of the detoxification pathway.

Discussion on absorption rate:

The dermal absorption of nonylphenol (NP) was tested in an ex vivo perfused porcine skin flap model (IPPSF). This model has earlier been shown to be a reliable tool to predict human exposure because of its intact vasculature, as well as anatomical and physiological similarities to human skin.

NP in aqueous PEG-400 solutions is absorbed at 0.1% of the applied dose after 8h, representing the amount of systemic available compound. It has been shown earlier that this rate was not significantly altered by using different vehicles (PEG-400 vs. water) or concentrations (0.1, 1.0, or 10%). The value is therefore considered to be valid also for higher concentrations.

About 0.75% of the applied dose penetrated the stratum corneum and underlying dermis within 8 h. In a worst case scenario all of the penetrated substance could subsequently be absorbed leading to an increased systemic exposure. This estimate does not account for a loss of stratum corneum due to exfoliation. However, the overall potential systemic exposure from skin contact to NP is still considerable less than 1%. This is in accordance with previous results from anin vitroporcine skin flow through (PSFT) diffusion cell assay. Due to the structural similarity between NP and 4-tert-octylphenol it is assumed that 4-tert-octylphenol shows a comparable low absorption rate.

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