Phenol

Endpoint summary

Description of key information

Oral exposure 
NOAEL = 300 mg/kg bw/day, systemic effects in rats
In a two generation drinking water reproductive toxicity study no relevant effects were observed up to 300 mg/kg bw in rats exposed over approx. 13 weeks. The NOAEL from a long-term drinking water (2a) study is 370 mg/kg bw/d in mice. Lower NOEL from 13 weeks study was not considered for risk assessment, as it is related to secondary effects due to reduced water and/or food intake.
Dermal exposure 
NOAEL =130 mg/kg bw/day systemic effects in rabbits
NOAEC = 2.37%, local effects in rabbits
In the dermal study conducted by Deichmann et al. (1950) rabbits showed local effects at a concentration of 3.56% and neurobehavioral effects (tremor) after repeated exposure to 260 mg/kg bw/day. The NOAEL was 130 mg/kg bw/day. The validity of this study concerning systemic effects is limited. 
Inhalation exposure 
NOAEC = 20 mg/m³, systemic effects in monkeys 
In a continuous inhalation study with rhesus monkeys, rats and mice no significant pathological effects were reported at 5 ppm (20 mg/m³) for 90 d. No adverse effects were reported in a valid 14 day-inhalation study in rats (Hoffman et al., 2001). The NOAEC for local and systemic effects was 96 mg/m³. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

20 mg/m³

Study duration:

subchronic

Species:

monkey

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

130 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Additional information

ORAL EXPOSURE

In long-term drinking water studies (NIH, 1980; robust study summary in IUCLID Section 7.7), 50 animals/sex/group of F344 rats and B6C3F1 mice were administered 2500 or 5000 mg/l (equivalent to 200 and 450 mg/kg bw/day for rats and 280 and 370 mg/kg bw/day for mice) for 103 weeks. Parameters on haematology, clinical biochemistry and urinanalysis were not investigated.
In both treatment groups of the rat study the water consumption was decreased (80% and 90% of control value, respectively) and in the high dose groups the body weight was reduced. No clinical signs of toxicity were recorded. No treatment related effects were detected in histopathological evaluation of non-neoplastic effects. Neoplastic effects were discussed in Section 7.7.
The reduction of body weight gain was attributed to the reduced water consumption, the NOAEL in rats is 450 mg/kg bw/day.
In mice of the low and high dose groups the body weight was reduced and water consumption was suppressed (75% and 50 -60% of control value, respectively). No clinical signs of toxicity were recorded except a reduced tendency to fight in treated males (no data about dose) . No treatment related effects were detected in histopathological evaluation of non-neoplastic and neoplastic effects. The reduction of body weight gain was attributed to the reduced water consumption, the NOAEL in mice is 370 mg/kg bw/day.

 

In a two generation drinking water reproductive toxicity study (Ryan et al., 2001; robust study summary in IUCLID Section 7.8.1) a subset of male Sprague-Dawley rats were administered concentrations of 0, 200, 1000 or 5000 mg/l (corresponding to 0, 15, 71 and 300 mg/kg bw/day) for approximately 13 weeks prior to assessing clinical chemistry, haematology and immunological parameters. In contrast to the concurrent positive control no significant effects were observed on spleen weight, cellularity (cells/spleen), or antibody-forming cells (no. of antibody producing plasma cells per spleen or per 10E6 cells) for any of the treated groups compared to the control group. No relevant effects were detected in haematology and clinical chemistry. For the parameters examined, the NOAEL was considered to be 300 mg/kg bw/day.

 

In a drinking water study related to neurotoxic effects (CMA, 1998; see robust study summary in IUCLID Section 7.9.1) 15 rats per dose per sex were exposed to 0, 200, 1000, or 5000 ppm for 13 weeks. Five rats/sex/group were used for the following phases of the study: perfusion after 13 weeks of treatment, perfusion at the end of the recovery period of 4 weeks, and necropsy at the end of the recovery period of 4 weeks.
At a concentration of 5000 ppm lower body weight, reduced food and water consumption and abnormal clinical signs including dehydrated appearance was reported; one female was sacrificed due to poor condition. At 1000 ppm, decreased water intake and on occasion dehydrated appearance were seen. Marked improvements were noted following recovery. No effects were noted for any parameters at 200 ppm. Neurobehavioral evaluations (functional observation battery) did not reveal any findings of neurotoxicological significance at any concentration following treatment or recovery. Observations of altered motor activity (females only) were noted, however, these findings were considered to be secondary to the reduction in water and/or food intake. No gross or histopathological lesions in nervous tissue attributed to treatment with phenol were detected. Based on these findings, a NOAEL for neurotoxicity under the conditions of this study was 5000 ppm (308 and 360 mg/kg bw/day for males and females, respectively). The overall study NOEL under the conditions of this study was 200 ppm (18 and 25 mg/kg bw/day for males and females, respectively). Conclusion: In male and female rats the NOAEL for neurotoxic effects was 5000 ppm in a 13 week drinking water study. The NOEL concerning overall effects was 200 ppm. However, this NOEL was not used for risk assessment, as it is related to secondary effects from reduced water and food intake.

In a subacute gavage study (Berman et al., 1995; see IUCLID Section 7.5.1; limited validity; 0, 4, 12, 40, and 120 mg/kg bw/day for 14 days) in female F344 rats it has been shown that the effect level (NOAEL presumably 4 mg/kg bw/day; 120 mg/kg bw/day was lethal for all rats) is clearly lower than in drinking water studies which might be related to the bolus effect.

 

In a subacute study (Hsieh et al., 1992, see IUCLID Section 7.5.1) male CD-1 mice were continuously exposed to 0, 4.7, 19.5, and 95.2 mg phenol/l drinking water (corresponding to 0, 1.8, 6.2, 33.6 mg/kg bw/day) for 4 weeks. In summary, hematological and neurochemical parameters were altered in male mice even at the lowest dose of 1.8 mg/kg bw/day, the toxicological relevance of the neurochemical effects are not clear; immunological parameters were affected at >= 6.2 mg/kg bw/day. LOAEL = 1.8 mg/kg bw/day. According to SCOEL (2003) the significance of these findings for human health is questionable, particularly as the surrounding database on repeated exposure studies by the inhalation or oral routes does not provide consistent and convincing evidence of appreciable immunotoxicity or neurotoxicity.

 

 

DERMAL EXPOSURE

In a subacute dermal study in rabbits (Deichmann et al., 1950; limited validity; see detailed documentation in Section 7.5.2) 4 albino rabbits per dose level received repeated dermal application 5 days per week for 18 days. The daily exposure duration was 5 hours. The phenol concentrations of test solutions were 1.18, 2.37, 3.56, 4.75, 5.93, and 7.12% in water corresponding to systemic dose levels of 130, 260, 390, 520, 650, and 780 mg/kg bw/day. Systemic effects like tremor were detected at 260 mg/kg bw/day, mild irritant effects at a concentration of 3.56% and severe local effects at 4.75%. Mortality (presumably due to systemic effects) was reported at 780 mg/kg bw/day. For systemic effects, the NOAEL was 130 mg/kg bw/day (LOAEL 260 mg/kg bw/day). The LOAEC for local effects was 3.56% aqueous solution and the NOAEL 2.37%.

There are no further valid data for the dermal route.

 

INHALATION EXPOSURE

Studies in experimental animals

 

In relation to the effects of long-term exposure, continuous inhalation exposure of rhesus monkeys, rats and mice to 5 ppm (20 mg/m³) phenol for 90 days resulted in no significant pathological effects (Sandage, 1961, see IUCLID Section 7.5.3). Although this was a well-designed and wide-ranging study, SCOEL felt that limited reporting of results, especially regarding irritation of the upper respiratory tract, was a difficulty. However, no significant systemic toxicity seems likely to have been produced in any of the three species at this level.

 

In a 14 day-inhalation study male and female F344 rats (n=20 per dose per sex; CMA, 1998 & Hoffman et al., 2001, see robust study summary in IUCLID Section 7.5.3) were exposed to phenol vapour by nose-only exposures for 10 exposures (5 days/week, 6 hours/day) at target concentrations of 0, 0.5, 5.0 and 25 ppm (0, 1.9, 19, 96 mg/m³). 10 rats/sex/group were sacrificed after 10 exposures, and after a 14-day recovery time for the remaining animals. No signs of toxicity in clinical observations (including neurological signs), body weights, food consumption, clinical chemistry, haematology, organ weights, macroscopic pathology or microscopic pathology were seen during the exposures or at either sacrifice interval. The NOAEC for local or systemic effects is 96 mg/m³.

 

In a subchronic study (Deichmann et al., 1944; limited validity; see detailed documentation in IUCLID Section 7.5.3) 15 rats were exposed 7 hours per day, 5 days per week for 74 day to 100 -200 mg/m³ (analytically verified). No clinical signs were observed during exposure period. No effects were detected at necropsy and in histopathological examination of liver, lung, kidney and heart. In summary, in this inhalation study of limited validity no adverse effects were found in rats exposed to 100-200 mg/m³. These data supported the results in the 2 -week inhalation study by Hoffman et al.(2001).

 

The results reported by Hoffman et al. (2001) are also confirmed by data presented in a toxicokinetic study (Dow, 1994; see detailed documentation in Section 7.1.1). Male F344 rats exposed 6 h/day for 8 days to 25 ppm (96 mg/m³; analytical concentration) did not show any clinical signs of intoxication; the threshold for saturation of metabolic conjugation was not reached at this dose level (no or minor amounts of free phenol in blood).

 

The 14 day-inhalation study in rats presented by Dalin and Kristoffersson (1974) is not considered for evaluation of this endpoint due to limited reliability.

Human data

In the study of Bone et al. (1976; see IUCLID Section 7.10.5) the authors measured the liberation of phenol by bacterial metabolism. A 24 h-urine sample was collected from each of 10 healthy volunteers; urinary phenol was measured by GC methods after enzymatic hydrolysis of conjugates. There was presumably no exposure of the volunteers to phenol except via the gut by bacterial metabolism. The mean excretion rate was 9.8 mg/day/person (ca. 160 µg/kg bw/day). Interindividual differences and day-to-day variations (demonstrated in further examinations in one woman and 2 men) were shown and might be related to nutrition (ingestion of proteins). In further in vitro experiments with isolated gut bacteria it has been shown that aerobic bacteria fed with tyrosine produced phenol. Conclusion: Phenol is detected in urine of non-exposed humans; the mean excretion rate is 9.8 mg/day/person (ca. 160 µg/kg bw/day). It is suggested that phenol is liberated in the gut of humans due to aerobic bacterial metabolism of amino acids (e.g. tyrosine). In two supporting studies (Renwick et al., 1988; Lawrie et al., 1987; see IUCLID Section 7.10.5) the urinary excretion of phenol conjugates was also shown.

In the study of Shamy et al. (1994; see IUCLID Section 7.10.1 for details) 20 workers were exposed to phenol alone; the time weighted average exposure was 5.4 ppm (21 mg/m³) and the mean duration of exposure was 13.2 +-6.6 (SD) years. The reference group (n=30) had the same demographic characters like age, educational status and socioeconomic status. In summary, workers exposed to a time weighted average of 21 mg/m³ showed significantly altered parameters in clinical chemistry and haematology along with a significantly increased amount of phenol excreted via the urine. These data suggested systemic hepatotoxic effects, the LOAEC is 21 mg/m³. According to SCOEL (2003) the study has some shortcomings, as only 20 workers were examined, it is not clear whether the exposure was only to phenol and how the exposure was measured.

 

Further supporting reports on humans (see IUCLID Section 7.10.3; Spiller et al., 1993; Baker et al., 1978; Merliss, 1972) with repeated oral, inhalative or dermal exposures to phenol described mucosal irritation, diarrhea, dark urine, weakness, muscle pain, central nervous depression, loss of appetite and body weight, liver toxicity resulting in a bad general state of health. In a case report weekly intramuscular injections for 37 and 18 weeks of a 10 ml solution of 25% dextrose, 25% glycerol, 2.5% phenol, and 47.5% sterile water mixed with 10 ml of 0.5% lidocaine resulted in extreme fatigue, chest pain and burning, dizziness, light-headedness and somnolence, memory loss, inability to concentrate, and instability of mood (Kilburn, 1994; cited in EU-RAR 2006).