COT statement on phenol: tolerable daily intake (oral) - October 2002

To help derive a Soil Guideline Value (SGV) for phenol, the COT were asked to recommend an appropriate No Observed Adverse Effect Level (NOAEL) and Tolerable Daily Intake (TDI) for oral exposure to phenol.

1. The United Kingdom Government is in the process of providing guidance on the health risks from contaminated land 1. The guidance provides land-use-specific Soil Guideline Values (SGVs) for a range of chemical contaminants. Phenol has been identified as a soil contaminant of possible concern. To help derive a SGV for phenol, we were asked to recommend an appropriate No Observed Adverse Effect Level (NOAEL) and Tolerable Daily Intake (TDI) for oral exposure to phenol.

Toxicology

2. In 1994, the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) agreed that phenol should be regarded as a somatic cell in-vivo mutagen. In 2000, the COM reviewed the available mutagenicity, toxicokinetic and metabolism data on phenol and agreed conclusions regarding risk of mutagenicity following ingestion, which are reproduced below:

i. Any risk to human health by ingestion would be likely to be greatly reduced by rapid conjugation and detoxification via the glutathione pathway. Furthermore mutagenicity also appeared to be positively related to peroxidase activity while catalase could also have a protective role. Actual systemic exposure levels in humans would be very much lower than levels at which positive results had been achieved in studies in animals .

ii. The Committee concluded that by the oral route there was potential for a threshold of activity based on the protective mechanism outlined at (i).

3. The most recent addition to the toxicological data on ingested phenol, suitable for consideration for the purposes of risk assessment, is the two-generation reproduction study (drinking-water) in Sprague-Dawley rats by Ryan et al., published in 2001 3. The study was conducted as part of a negotiated consent agreement between the United States Environmental Protection Agency and the Phenol Panel of the Chemical Manufacturers Association. It was consistent with previous studies in finding evidence of parental and fetal toxicity at a dose of approximately 310 mg/kg bw/day. At the two lower doses (about 14 and 70 mg/kg bw/day), the only notable findings were reductions in absolute and relative prostate and uterine weights in the F1 generation. The authors argued that, given the absence of functional reproductive effects or adverse histological changes at these doses, the reductions in prostate and uterine weight did not represent an adverse effect of phenol. We note that this view is also consistent with the absence of effects on these organs in the NCI 1980 103-week drinking-water studies in F344 rats and B6C3F1 mice 4. The authors therefore proposed 70 mg/kg bw/day as the NOAEL in this study. In the light of this proposed NOAEL, the following paragraphs discuss several earlier studies which reported findings at lower doses.

4. Hsieh et al. (1992) reported a reduced red cell count and haematocrit in male CD-1 mice at 1.8, 6.2 and 34 mg/kg bw/day for 28 days (via drinking-water), and suppressed antibody production response at their two highest doses 5, but Ryan et al. (2001) found no such changes at comparable and higher doses, and longer duration of dosing, in male Sprague-Dawley rats 3. We note that the paper by Hsieh et al. provided no information on impurities in the reagent grade phenol used in the study, and did not indicate that any precautions had been taken to minimise oxidation and degradation of the test substance.

5. Hsieh et al. (1992) also reported reductions in neurotransmitter levels in several brain regions, in their study on male CD-1 mice 5. No other study has examined these endpoints, and the functional significance of the reported reductions is unknown. Moser et al. (1995) reported a change in behaviour (increased "rearing") in a battery of neurobehavioural tests in female F344 rats given phenol by gavage at 40 mg/kg bw/day for 14 days; again, the functional significance is unknown 6. In contrast, no relevant dose-related clinical or neuropathological findings were reported in the NCI 1980 103-week drinking-water studies in F344 rats and B6C3F1 mice, at much higher doses 4.

6. According to the USEPA online chemical toxicity information service 7, an unpublished 1945 Dow Chemical Company study revealed liver changes in rats (strain unknown) given phenol by gavage at 72 mg/kg bw/day for 6 months, and kidney damage at this dose and at 36 mg/kg bw/day, but no further details are available to us, and no useful conclusions can be drawn. The study by Berman et al. (1995) reported renal and hepatic pathology in female F344 rats given phenol for 14 days by gavage at 40 mg/kg bw/day, and thymic necrosis was found at 12 and 40 mg/kg bw/day 8. In contrast, no gross pathology in these three organs was reported by Hsieh et al. (1992) in male CD-1 mice at 34 mg/kg bw/day (via drinking-water) for 28 days 5. No histopathological changes in these organs were reported in the NCI 1980 (F344 rats, B6C3F1 mice) 4 and Ryan et al. (2001) (Sprague-Dawley rats) 3 drinking-water studies for longer periods at much higher doses. We note, however, that the thymus was not one of the tissues routinely examined microscopically in the NCI 1980 study.

7. Narotsky and Kavlock (1995) reported "altered respiration (eg rales and dyspnoea)" and "severe respiratory signs" in F344 rat dams given phenol by gavage at 40 and 53.3 mg/kg bw/day on days 6-19 of pregnancy 9. No similar finding was reported in other studies (eg NCI, 1980 and Ryan et al., 2001) 4, 3, and it may be that problems with gavage, rather than intragastric phenol, were responsible. This may also explain the litter losses at these doses in this study, since all of the dams that fully resorbed their litters experienced severe respiratory effects. Comparable fetal and maternal toxicity were not seen at higher doses in the gavage studies by Jones-Price et al. (Sprague-Dawley rats; CD-1 mice) 10,11 or in the Ryan et al. drinking-water study (Sprague-Dawley rats) 3.

8. The reasons for the apparent discrepancies between studies are unclear, but may be related to factors such as manner of exposure (abnormal findings reported at lower doses when phenol is administered as bolus doses by gavage than in studies using administration via drinking-water) and impurities, including oxidation and degradation products, in the test agent.

Conclusions

9. We note the opinion of the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (2000) that, by the oral route, there is potential for a threshold of activity for the mutagenicity of phenol.

10. The data which we have considered on the toxicity of ingested phenol are sufficient to identify a No Observed Adverse Effect Level (NOAEL) for other endpoints. The critical study is the enhanced two-generation reproductive and developmental toxicity study in rats, by Ryan et al. (2001), in which the overall NOAEL was 70 mg/kg bw/day 3. Although several studies have reported abnormal findings in animals at lower doses, these results were not consistent with the absence of comparable or related findings in other well-conducted studies at higher doses and longer periods of exposure to ingested phenol.

11. Standard uncertainty factors of 10 for extrapolation from rodent data, and 10 for variability within the human population, are appropriate.

12. The Tolerable Daily Intake for ingested phenol is therefore 0.7 mg/kg bw/day.

October 2002
COT Statement 2002/03

References

1. DEFRA/EA (2002) Department of the Environment, Food and Rural Affairs and the Environment Agency. Contaminants in soil: collation of toxicological data and intake values for humans. R&D Publication CLR 9. Environment Agency, Bristol.

2. COM (2000) Department of Health. Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment. Statement on the mutagenicity of hydroquinone and phenol. COM/00/S1.

3. Ryan B M, Selby R, Gingell R, Waechter J M, Butala J H, Dimond S S, Dunn B J, House R, Morrissey R (2001). Two-generation reproduction study in immunotoxicity screen in rats dosed with phenol via the drinking water. Int J Toxicol 20, 121-142.

4. NCI (1980) National Cancer Institute. Bioassay of phenol for possible carcinogenicity. Technical Report TR-203. Prepared by the NCI for the National Toxicology Program , Research Triangle Park, NC, USA.

5. Hsieh G C, Sharma R P, Parker R D R, Coulombe R A (1992). Immunological and neurobiochemical alterations induced by repeated oral exposure of phenol in mice. European Journal of Pharmacology - Environmental Toxicology and Pharmacology Section 228, 107- 114.

6. Moser V C, Cheek B M, MacPhail R C (1995). A multidisciplinary approach to toxicological screening. III. Neurobehavioral toxicity. J Toxicol Environ Health 45, 173- 210.

7. USEPA (2001) United States Environmental Protection Agency. Phenol. Integrated Risk Information System (IRIS, the USEPA online chemical toxicity information service). Accessed August 2002.

8. Berman E, Schlicht M, Moser V C, MacPhail R C (1995). A multidisciplinary approach to toxicological screening: I. Systemic toxicity. J Toxicol Environ Health 45, 127- 143.

9. Narotsky M G, Kavlock R J (1995). A multidisciplinary approach to toxicological screening. II. Developmental toxicity. J Toxicol Environ Health 45, 145-171.

10. Jones-Price C, Kimmel C A, Ledoux T A, Reel J R, Langhoff-Paschke L, Marr M C (1983a). Final study report - teratologic evaluation of phenol (CAS No. 108-95-2) in CD-1 mice (NTP Study No. TER-80-129). Research Triangle Institute, Research Triangle Park, NC, USA (NTIS Report No. PB85-104461).

11. Jones-Price C, Kimmel C A, Ledoux T A, Reel J R, Fisher P W, Langhoff-Paschke L, Marr M C (1983b). Final study report - teratologic evaluation of phenol (CAS No. 108-95-2) in Sprague-Dawley rats (NTP Study No. TER-81-104). Research Triangle Institute, Research Triangle Park, NC, USA (NTIS Report No. PB83-247726).