Phenol

Carcinogenicity

Description of key information

1) Phenol is not considered to be a carcinogen in experimental animals after repeated oral exposure (compare also with EU-RAR, 2006). 
2) In most studies in experimental animals phenol has no carcinogenic activity after repeated dermal exposure. Only benign skin tumors were found after repeated dermal application of phenol concentrations inducing severe skin lesion due to the corrosive properties. 
3) There is evidence for promoting activity of phenol after repeated dermal application at concentrations inducing severe local effects due to the corrosive properties. 
4) There is no evidence for carcinogenicity in epidemiology. 

Justification for classification or non-classification

The available data indicated that classification for carcinogenicity is not warranted.

Additional information

CARCINOGENICITY IN EXPERIMENTAL ANIMALS

This endpoint is presented in Section 4.1.2.8 of the EU-RAR (2006; page 126). In the EU-RAR it was concluded that phenol is considered not to be a carcinogen in animals.

 

- Long-term oral studies in mice and rats (NIH, 1980; see robust study summaries in IUCLID Section 7.7)

Male and female B6C3F1 mice were exposed to 0, 2500 or 5000 ppm phenol in the drinking water (ca. 280 and 370 mg/kg bw/day). In low and high dose groups the body weight was reduced and water consumption was suppressed to 75% and 50-60% of control value, respectively. Histopathology revealed no treatment related non-neoplastic and neoplastic. Phenol was not toxic or carcinogenic for male or female B6C3F1 mice.

Male and female F344 rats exposed to the same concentrations in the drinking water ingested ca. 200 and 450 mg/kg bw/day, respectively. In both treatment groups the water consumption was decreased (80% and 90% of control value, respectively) and in the high dose groups the body weight was reduced. No treatment related effects were detected in histopathological evaluation of non-neoplastic effects. The incidence of leukaemia or lymphomas, adrenal pheochromocytomas, thyroid c-cell carcinomas (not significant when combined with c-cell adenomas), and interstitial cell tumours of the testes (high spontaneous rate) was significantly increased only in male rats that received 2,500 ppm phenol, no such effect could be observed in the high dose males. The lack of increased tumour incidences in the high dose group and the statistical analyses indicate that the increased neoplastic incidences in males of the low dose group is not considered by the authors to be associated with the administration of phenol. No increased tumour incidences were found in female rats. It is concluded that phenol was not carcinogenic for male or female F344 rats.

 

- Dermal exposure

In the study of Boutwell & Bosch (1959, see robust study summary in IUCLID Section 7.7) mice received twice weekly 1 drop of 10% phenol in benzene (known carcinogen) on the skin; increased tumour incidences were observed. However, the study is insufficient for evaluation of carcinogenic effects of phenol after dermal exposure using benzene as vehicle.

Medium-term dermal treatment (20 weeks) of phenol (3 mg/mouse in 200 µl acetone, twice weekly) in FVB/N wildtype mice or its transgenic mouse line TG.AC carrying a v-Ha-ras gene revealed no increase of skin tumours in wildtype or transgenic mice (but inhibition of hair growth and chronic skin irritation) (Spalding et al., 1993 and Tennant et al., 1995, see IUCLID Section 7.7 or EU-RAR 2006, page 127).

No tumours were detected in 20 mice after weekly dermal application of 100 µl 5% phenol in acetone (5 mg phenol/application; local effects but not clearly specified; same skin area exposed every 2nd week) for 32 weeks. Using the same exposure duration of 32 weeks but 25µl 20% phenol (also 5 mg/application; corrosive effects; same skin area treated every 4th week) 7 out of 18 mice showed papillomas but not carcinomas (Salaman & Glendenning, 1957, cited in MAK, 1998, see additional information in IUCLID Section 7.7).

 

- Promoting activity of phenol

In the study of VanDuuren et al. (1968, see detailed documentation in IUCLID Section 7.7) 20 female ICR/Ha Swiss mice per group received 14 d after initiation with 150 µg 7,12 -dimethylbenz(a)anthracene in 0.1 ml acetone (single dermal exposure) thrice weekly dermal applications of 3 mg phenol in 0.1 ml acetone for 1 year or only the solvent acetone (control). A slight increase in papillomas (cumulative incidence: 4/20; carcinomas 1/20) was detected which is not considered to be of toxicological relevance compared with controls (2/20 papillomas and 1/20 carcinoma). In this study phenol has no promoting activity after dermal exposure.

Boutwell & Bosch (1959, see detailed documentation in IUCLID Section 7.7) reported promoting experiments in mice which were not considered to be usable for evaluation of promoting activity since benzene (known carcinogen) was used as vehicle. However, in further experiments reported in this study acetone was used as vehicle for initiator and promoter (not carcinogenic like benzene). 20-24 female mice of unknown strain were initiated with 75µg DMBA/mouse; for promoting 10 or 20% phenol were used which resulted in severe local effects and promoting activity. No such effects were found with the vehicle control (DMBA treated). In summary, there is evidence for promoting activity of phenol at concentrations inducing severe local effects due to the corrosive properties.

In skin promoting experiments Salaman & Glendenning (1957, cited in MAK, 1998) treated 20 mice with 0.3 mg dimethylbenz[a]anthracene in acetone for initiation followed by weekly dermal application of 5% (local effects but not clearly specified) or 20% (corrosive effects) phenol in acetone; the same skin area was exposed every 4th week (20% phenol) or every 2nd week (5%). Dose dependent increase in tumour incidences was reported. However, no data are available on DMBA control without subsequent phenol treatment.

 

EPIDEMIOLOGY

In the EU-RAR (2006, page 127) only the study of Kauppinen et al. (1986; see IUCLID Section 7.10.2) was documented; it was noted that the relative risk of phenol was confounded by exposure to pesticides. When workers exposed to phenol and pesticides were excluded, the odd ratios decreased to a non-significant level. There are no further data revealing an association of phenol exposure to increased tumour rates in humans. As mentioned above no firm conclusion on risk levels could be drawn from the available data due to shortcomings like co-exposure to other chemicals (Kauppinen et al., 1993; Blair et al., 1990; Dosemeci et al., 1991), or the studies gave no significant increase in the tumour incidences (Pottern et al., 1992)(studies cited in MAK, 1998; see also IUCLID Section 7.10.2).