Phenol

Endpoint summary

Additional information

Toxicokinetics & Metabolism

These data are presented in the EU-RAR (2006; see also Section 13) in Section 4.1.2.1 (page 77ff). It is summarized in the EU-RAR that:

1) Phenol is well absorbed via gastrointestinal and respiratory tract and the dermal route

2) In body tissues phenol is rapidly distributed

3) It is metabolised to sulfate and glucuronide conjugates

4) Excretion via urine is the main elimination pathway.

Key studies (robust study summaries in IUCLID Section 7.1.1)

In the valid study presented by Dow (1994) toxicokinetic parameters as well as metabolism was investigated after oral and inhalation exposure. Male and female F344 rats were exposed to single and repeated (8 days) doses of 14C-phenol by gavage: 1.5, 15, 150 mg/kg; drinking water: 5000 ppm, and inhalation: 25 ppm, 6 hours per day. For all exposure routes radioactivity was rapidly eliminated in urine (>90% in 24 hours), only 1 -3% via faeces and traces via expiration; less than 1% remained in tissues and carcass. After gavage of jugular vein cannulated animals with 150 mg/kg bw, peak concentrations of 46 µg free phenol/g blood were observed within 1 min, declining to 1 µg/g blood by 60 min (half-life =12 min). Muscle twitching also developed rapidly in these animals and disappeared by 45 minutes as blood levels of phenol declined. The threshold concentration for systemic clinical effects is considered to be 5 -17 µg free phenol/g blood.Free phenol was not detected in blood during inhalation exposures and clinical effects were absent (as well as in drinking water studies). The urinary metabolite profile, predominantly conjugates of phenol, was dose dependent. The ratio of glucuronide/sulfate conjugates of phenol was 0.61 after 1.5 or 15 mg/kg bw and rose to 1.16 after 150 mg/kg bw. Thus, the saturation of sulfate conjugation results in predominance of the glucuronide conjugate. Metabolic profiles obtained after drinking water were equivalent to the high dose gavage profile, while profiles after inhalation resembled the low dose gavage profile. Male and female rats were equivalent inallstudies. These studies support the conclusion that free phenol in blood and associated clinical toxicology are seen only at doses that saturate the conjugation pathways.

Conclusion: In oral and inhalation studies phenol is rapidly absorbed and metabolised mainly to sulfate and glucuronide conjugates of phenol. More than 90% of the applied radioactivity is excreted via urine within 24 h after exposure, minor amounts were excreted via faeces or were found in tissues and carcass at termination.

Female F344 rats (n=3 -4 per group) received 0.03 mg/kg bw 14C-labelled phenol via oral (gavage), dermal, intratracheal, or i.v. administration. Radioactivity in urine and feaces was analysed after sampling in metabolism cages; the animals were sacrificed 72 h after application and radioactivity in organs, carcass and washings determined. Rapid and complete absorption of the administered radioactivity was found after oral and intratracheal exposure: 70-85% of the recovered dose was excreted in urine 4h after administration and urinary elimination was essentially complete by 12 h, after 72 h totally 95% of the applied dose were excreted via urine and only 1 -3% were excreted via faeces. Slightly reduced absorption rates were detected after dermal application: total amount of applied radioactivity excreted via urine was 75%, 3% were measured in faeces, 14% in skin washing at 72 h, 2% in the treated skin, and 2.5% in plastic blisters. The total dermal absorption rate was ca. 80% of the applied dose. Independent on the route of exposure low amounts (1 -3% of the recovered dose) retained in the rat 72 h after application. Phenol was distributed throughout the body. At a dose level of 0.033 mg/kg bw phenol was metabolized in rats to the sulphate (main metabolite) and glucuronide conjugates after absorption from the four routes of exposure (Hughes & Hall, 1995).

Conclusion: The oral, dermal, intratracheal, and i.v. exposure to phenol results in its rapid absorption, conjugation and elimination via urine.

 

Three volunteers ingested a single oral dose of 0.01 mg 14C-labelled phenol/kg bw and 17 mammalian species plus chicken received orally the labelled phenol one-time at dose levels between 20 and 50 mg/kg bw. Metabolites were determined in 24h-urine by radiochromatogram scanning. Four peaks which corresponded to phenylsulphate, phenylglucuronide, hydroquinone (quinol) monosulphate and hydroquinone monoglucuronide were detected. Catechol conjugates did not appear to be formed in sufficient quantities. In three men 90% of an oral dose was excreted in 24 h mainly as phenylsulphate (77% of 24 h excretion) and phenylglucuronide (16%) with very small amounts of hydroquinone sulphate and glucuronide. The above four metabolites of phenol were also detected in the urine of the following species: rat, mouse, jerboa, gerbil, hamster, lemming, and guinea pig. Three metabolites were excreted by some species, namely, phenol and quinol glucuronides and phenylsulphate by the squirrel monkey and capuchin monkey, and phenol and quinol sulphates and phenylglucuronide by the ferret, dog, hedgehog and rabbit. Only 2 metabolites were excreted by the rhesus monkey, fruit bat and hen (phenylsulphate and phenylglucuronide) and by the cat (phenyl sulphate and hydroquinone sulphate). One metabolite (phenyl glucuronide) only was excreted by the pig. In humans 90% (range 85 -98) of the applied dose was excreted via the 24 h-urine indicating nearly complete oral absorption. Similar results were obtained with rats (Capel et al., 1972).

Conclusion: Significant species differences in metabolism of phenol has been shown. Humans and rats showed similar metabolic pathways and quantities of metabolites in urine. Comparing 18 different mammalian species including humans highest absorption rates were found in humans and rats after oral application. The rat is likely a good surrogate for human metabolism of phenol.

 

Further supporting data on absorption (see IUCLID Section 7.1) are reported by

Kao et al., 1979

Piotrowski, 1971.

Further supporting data on distribution (IUCLID Section 7.1) are reported by

Liao and Oehme, 1981.

Further supporting data on metabolism (IUCLID Section 7.1) are reported by

Cassidy and Houston, 1980

Houston and Cassidy, 1982

Cassidy and Houston, 1984

Kenyon et al., 1995

Kim et al., 1995.

Further supporting data on excretion (IUCLID Section 7.1) are reported by 

Deichmann, 1944

Kao et al., 1979.

Piotrowski, 1971.

 

Conclusions

After oral and inhalation exposure phenol was rapidly and completely absorbed, an absorption rate of 100% can be assumed for risk assessment. A slightly lower absorption rate has been found for the dermal route; in rats approximately 80% of the applied dose was absorbed. In body tissues phenol was rapidly distributed. Free phenol was detected in the blood only at high doses after saturation of metabolic conjugation; the highest concentration of free phenol in blood was measured 1 min after gavage of 150 mg/kg bw, the half-life was 12 minutes. Clinical signs of toxicity were associated with the concentration of free phenol in blood, a threshold concentration of 5 -17 µg/g blood was estimated. From a variety of case reports (see Summary in Section 7.2) it is known that liquid phenol in contact with the skin rapidly enters the bloodstream.

In comparative studies (18 different species plus humans) it has been shown that the metabolism and excretion profile was very similar in rats and humans. Phenol was metabolised mainly to sulfate and glucuronide conjugates and minor amounts were metabolized to hydroquinone and conjugated with sulfate or glucuronide.

The ratio of phenyl glucuronide/phenyl sulfate conjugates rose with increasing doses (gavage of 150 mg/kg bw in rats) suggesting the saturation of sulfate conjugation which resulted in predominance of the glucuronide conjugate.

In toxicokinetic studies phenol and phenol conjugates are mainly excreted via urine (>90%), only minor amounts via faeces (1 -3%) and 24 h after bolus exposure less than 1% were detected in tissues and carcass.

 

Summary

1) Phenol is rapidly absorbed, metabolized via conjugation, and excreted via urine.

2) Free phenol in blood and associated clinical toxicology are seen only at doses that saturate the conjugation pathways.

3) The rat is likely a good surrogate for human toxicokinetic & metabolism of phenol.

4) For risk assessment purposes the rates of oral and inhalation absorption are assumed to be 100%, whereas for dermal exposure the rate was set to 80%.