Phenol

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study is comparable to OECD guideline 451 with acceptable restrictions (carcinogenicity study, limited parameters tested concerning repeated dose toxicity; no 3rd dose level; oesophagus, musculature, peripheral nerve, spinal cord, eyes were not examined histopathologically; no data about change of test substance solutions in drinking water).

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Bioassay of phenol for possible carcinogenicity.Report of the National Cancer Institute

Author:

NIH

Year:

1980

Bibliographic source:

NIH Publication No. 80-1759

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 451 (carcinogenicity study)

Deviations:

yes

Remarks:

(no 3rd dose level; in histopathology some organs recommended in OECD451 were not evaluated)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenol

EC Number:

203-632-7

EC Name:

Phenol

Cas Number:

108-95-2

Molecular formula:

C6H6O

IUPAC Name:

phenol

Details on test material:

Reagent grade; Lot No. 79380 from Textile Chemical Company,. Reading, Pa; melting point and elemental analyses close to literature and with theoretical values.
Purity 98.47% (U.S.P. titration method, U. S. Pharmacopeia, 1975).

Pilot study:
United States Pharmacopoeia grade Lots No. A4X and B4A from Eastman Kodak Company, Rochester, N. Y.; melting point and elemental analyses close to literature and with theoretical values.

All batches:
storage at room temperature in original containers

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: NCr Frederick Cancer Research Center (Frederick, Maryland)
- Age at study initiation: 5-6 weeks
- Fasting period before study: no
- Housing: three per cage
- Diet and drinking water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-50
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

other: tap water

Details on oral exposure:

Test solutions prepared by completely dissolving weighed amount of phenol in a measured volume of tape water; solution diluted to the desired final volume specified concentrations.
No further data.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the test solutions analyzed by gas chromatography: mean concentration of eight samples (nominal 5000 ppm) was 5,237+-509 ppm

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

daily ad libitum

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 2500, 5000 ppm
Basis:
other: nominal in water; analytical concentration of the high dose: 5237+-509 ppm

Doses / concentrations 2

Remarks:

Doses / Concentrations:
ca. 200 and 450 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

Controls in the same room; no further details
post exposure observation period: 1-2 weeks

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Observations of animals twice daily; clinical signs and palpable masses (tumours) recorded weekly; mean body weights and food consumption reported every 2 weeks for the first 12 weeks and then monthly; water consumption recorded weekly.

Sacrifice and pathology:

Moribund animals & survivors at termination killed by i.p. sodium pentobarbital; necropsy performed.
Histopathology
All gross lesions plus the following organs examined microscopically: skin, lungs and bronchi, trachea, bone and bone marrow, spleen, lymph nodes, heart, salivary gland, liver, pancreas, stomach, small intestine, large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, mammary gland, prostate or uterus, testis or ovary, and brain. Occasionally, additional tissues also examined (no further data).

Other examinations:

no

Statistics:

Survival:
product-limit procedure of Kaplan and Meier (1958); statistically censored; dose-related effect using the method of Cox (1972) for testing two groups for equality and
Tarone's (1975) for testing for a dose-related trend.
All paramters:
One-tailed P values, exception: departure from linearity test, which is reported only when its two-tailed P value is less than 0.05.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No effects

BODY WEIGHT AND WEIGHT GAIN
At >= 20 weeks of exposure mean body weight was lower in the high dose groups than those of the controls.

WATER CONSUMPTION AND COMPOUND INTAKE
Water consumption of the low- and high-dose groups was 80% and 90% of control value, respectively (comment: no reporting error; compare with dose actual ingested).

GROSS PATHOLOGY
No effects reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
The inflammatory, degenerative, and hyperplastic lesions were similar in number and kind to those that naturally occur in aged F344 rats.
HISTOPATHOLOGY: NEOPLASTIC
no effects; see Section 7.7

Effect levels

1

Dose descriptor:

LOEL

Effect level:

2 500 ppm

Sex:

male/female

Basis for effect level:

other: reduced water consumption (200 mg/kg bw/day)

2

Dose descriptor:

LOEL

Effect level:

5 000 ppm

Sex:

male/female

Basis for effect level:

other: reduced body weight (450 mg/kg bw/day)

3

Dose descriptor:

NOAEL

Effect level:

5 000 ppm

Sex:

male/female

Basis for effect level:

other: corresponding to 450 mg/kg bw/day; NOAEL because reduced body weight related to reduced water consumption; limited number of parameters tested (carcinogenicity study)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a chronic drinking water study in rats phenol resulted in reduced water consumption and secondary in reduced body weight gain. The NOAEL was 5000 ppm or 450 mg/kg bw/day.

Executive summary:

The study is comparable to OECD guideline 451 with acceptable restrictions (carcinogenicity study, limited parameters tested concerning repeated dose toxicity; no 3rd dose level; oesophagus, musculature, peripheral nerve, spinal cord, eyes were not examined histopathologically; no data about change of test substance solutions in drinking water).

In a 103 -weeks cancer studies on male and female F344 rats (n=50 per dose per sex) animals were exposed to 0, 2500 or 5000 ppm phenol (purity 98.5%) in the drinking water (ca. 200 and 450 mg/kg bw/day). 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 clinical signs of toxicity were recorded. No treatment related effects were detected in histopathological evaluation of non-neoplastic effects. No treatment-related increased tumour incidences were found (see Section 7.7).

Conclusion: In a chronic drinking water study in rats phenol resulted in reduced water consumption and secondary in reduced body weight gain. The NOAEL was 5000 ppm or 450 mg/kg bw/day.