2-phenoxyethanol

Carcinogenicity

Description of key information

Two repeated dose (104 weeks) OECD 451 and GLP compliant studies in rats and mice, respectively, are available. The available data indicate that 2-phenoxyethanol is not carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

No English test report is available (study in Japanese), but an English summary and all tables and figures in English are available.

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-Phenoxyethanol
- Physical state: colorless clear liquid
- Batch: PKF5373
- Purity: 99.8-99.9%

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test substance was analyzed for purity and stability by both infrared spectrometry and high performance liquid chromatography before and after its use. The concentrations of the substance in drinking water were determined by high performance liquid chromatography at the time of preparation, and on the 5th day after preparation, while stored at room temperature. Stability of the test material for the duration of use in the study was confirmed.

Duration of treatment / exposure:

2 years (104 weeks)

Frequency of treatment:

Daily, the test substance was administered to the drinking water.

Dose / conc.:

2 500 mg/L drinking water

Dose / conc.:

5 000 mg/L drinking water

Dose / conc.:

10 000 mg/L drinking water

Dose / conc.:

124 mg/kg bw/day (actual dose received)

Remarks:

male

Dose / conc.:

249 mg/kg bw/day (actual dose received)

Remarks:

male

Dose / conc.:

510 mg/kg bw/day (actual dose received)

Remarks:

male

Dose / conc.:

191 mg/kg bw/day (actual dose received)

Remarks:

female

Dose / conc.:

380 mg/kg bw/day (actual dose received)

Remarks:

female

Dose / conc.:

795 mg/kg bw/day (actual dose received)

Remarks:

female

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest dose level was chosen so as not to exceed the maximum tolerated dose (MTD), based on both growth rate and toxicity in the previous 13-week toxicity study.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: The animals were observed daily for clinical signs and mortality.

FOOD CONSUMPTION, WATER CONSUMPTION AND BODY WEIGHT:
- Time schedule for examinations: once a week the first 13 weeks and every 4 weeks thereafter.

HAEMATOLOGY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the 2 year study for the terminal necropsy.
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: Yes, overnight.
- How many animals: Haematology was examined in 36, 37, 44, and 39 male rat from the control, 2500, 5000, and 10000 mg/L dose groups, respectively. 38, 39, 38, and 41 female rat were examined from the control, control, 2500, 5000, and 10000 mg/L dose groups, respectively.
- Parameters: Red blood cell count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, reticulocytes, white blood cell count, and differential white blood count.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: The surviving animals were bled at the end of the 2 year study for the terminal necropsy.
- Animals fasted: Yes, ether
- How many animals: Haematology was examined in 36, 37, 44, and 39 male rat from the control, 2500, 5000, and 10000 mg/L dose groups, respectively. 39, 39, 38, and 41 female rat were examined from the control, 2500, 5000, and 10000 mg/L dose groups, respectively.
- Parameters: Total protein, albumin, A/G ratio, total bilirubin, glucose, total cholesterol, triglyceride, phospholipid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyl transpeptidase, creatine kinase, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, and inorganic phosphorus.

URINALYSIS:
- Time schedule for collection of urine: Near the end of the administration period
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters: pH, protein, glucose, ketone body, bilirubin, occult blood, and urobilinogen.

Sacrifice and pathology:

Animals found dead, in a moribund state, or surviving to the end of the 2-year administration period underwent complete necropsy.
GROSS PATHOLOGY: Yes, organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy.

HISTOPATHOLOGY: Yes, both non-neoplastic and neoplastic lesions. The organs and tissues were fixed and embedded in paraffin. Tissue sections of 5 μm thick were prepared and stained with hematoxylin and eosin and examined for histopathology

Statistics:

Incidences of neoplastic lesions were statistically analyzed by Fisher’s exact test. A positive trend of the dose-response relationship for the neoplastic incidence was analyzed by Peto’s test. Incidences of non-neoplastic lesions and urinalysis were analyzed by Chi-square test. Changes in body weight, water consumption, food consumption, hematological and blood biochemical parameters, and organ weights were analyzed by Dunnett’s test.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Males dosed with 10000 mg/L test substance and in all the test substance administered female groups, soiled fur around genitalia was observed.

Description (incidence):

The survival rate was not significantly different between the substance administered groups and the control group.

Description (incidence and severity):

Growth rates of the 10000 mg/L administered males and all the test substance administered female groups were suppressed, as compared with the respective controls. Terminal body weights of the 2500, 5000 and 10000 mg/L administered groups were 98%, 98% and 94% for males, and 95%, 96% and 89% for females, as compared with the respective controls.

Description (incidence and severity):

Decrease in food consumption was observed in the 10000 mg/L administered males and in all the test substance administered female groups compared to the control groups.

Description (incidence and severity):

Decrease in water consumption was observed in the 5000 and 10000 mg/L male dose groups and in all the test substance administered female groups during the first year. Male mean water consumption during 104 weeks was in the range of 91-109%, 87-111%, and 77-115% compared to the control group for 2500, 5000 and 10000 mg/L dose groups, respectively. Female mean water consumption during 104 weeks was in the range of 75-112%, 72-102%, and 63-116% compared to the control group for 2500, 5000 and 10000 mg/L dose groups, respectively.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

A statistically significant increase in mean corpuscular volume and mean corpuscular haemoglobin concentration was measured in females dosed with 10000 mg/L. Mean corpuscular haemoglobin was decreased in males of the low dose group. The mean corpuscular haemoglobin results in males were not dose response related.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Increases in ALT and AST and decreases in total protein and creatinine were found in males dosed with 10000 mg/L. In females increased bilirubin and urea nitrogen and decreased triglycerides were observed in the high dose group. All these effects were considered to be not toxicological relevant since changes were marginal.

Description (incidence and severity):

Lowered urinary pH and decreases in urinary protein and the incidence of positive ketone body in urine were noted in the 10000 ppm-administered females. The lowered urinary pH might be caused by phenoxyacetic acid, a urinary metabolite of 2-phenoxyethanol.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

In male rats, adrenal relative weights were increased at all dose levels, but absolute weights were only increased in the low and mid dose group. Relative kidney and brain weights were observed in the high dose group. In females, absolute adrenal weight was decreased while absolute kidney weight was increased in the high dose group. Relative heart, kidney and brain weights were increased in the high dose group. Relative ovary weights were increased in the low and high dose group. In the absence of histopathological findings (except for increased relative kidney weights in male rats) these organ weight changes are considered to be of no toxicological relevance.

Description (incidence and severity):

Increased incidence and severity of renal pelvis urothelial hyperplasia and an increased incidence of renal papillary mineralization and necrosis was found in males of the high dose group. The observed histopathological effects in males were slight to moderate. In females no histopathological changes were observed.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Neoplastic histopathological changes were not found.

Details on results:

CLINICAL SIGNS AND MORTALITY
The survival rate was not significantly different between the substance administered groups and the control group. Males dosed with 10000 mg/L test substance and in all the test substance administered female groups, soiled fur around genitalia was observed.

BODY WEIGHT AND WEIGHT GAIN
Growth rates of the 10000 mg/L administered males and all the test substance administered female groups were suppressed, as compared with the respective controls. Terminal body weights of the 2500, 5000 and 10000 mg/L administered groups were 98%, 98% and 94% for males, and 95%, 96% and 89% for females, as compared with the respective controls.

FOOD AND WATER CONSUMPTION
Decrease in food consumption was observed in the 10000 mg/L administered males and in all the test substance administered female groups compared to the control groups. Decrease in water consumption was observed in the 5000 and 10000 mg/L male dose groups and in all the test substance administered female groups during the first year. Male mean water consumption during 104 weeks was in the range of 91-109%, 87-111%, and 77-115% compared to the control group for 2500, 5000 and 10000 mg/L dose groups, respectively. Female mean water consumption during 104 weeks was in the range of 75-112%, 72-102%, and 63-116% compared to the control group for 2500, 5000 and 10000 mg/L dose groups, respectively

HAEMATOLOGY AND CLINICAL CHEMISTRY
A statistically significant increase in mean corpuscular volume and mean corpuscular haemoglobin concentration was measured in females dosed with 10000 mg/L. Mean corpuscular haemoglobin was decreased in males of the low dose group. The mean corpuscular haemoglobin results in males were not dose response related. Increases in ALT and AST and decreases in total protein and creatinine were found in males dosed with 10000 mg/L. In females increased bilirubin and urea nitrogen and decreased triglycerides were observed in the high dose group. All these effects were considered to be not toxicological relevant since changes were marginal.

URINALYSIS
Lowered urinary pH and decreases in urinary protein and the incidence of positive ketone body in urine were noted in the 10000 ppm-administered females. The lowered urinary pH might be caused by phenoxyacetic acid, a urinary metabolite of 2-phenoxyethanol.

ORGAN WEIGHTS
In male rats, adrenal relative weights were increased at all dose levels, but absolute weights were only increased in the low and mid dose group. Relative kidney and brain weights were observed in the high dose group. In females, absolute adrenal weight was decreased while absolute kidney weight was increased in the high dose group. Relative heart, kidney and brain weights were increased in the high dose group. Relative ovary weights were increased in the low and high dose group. In the absence of histopathological findings (except for increased relative kidney weights in male rats) these organ weight changes are considered to be of no toxicological relevance.

HISTOPATHOLOGY: NON-NEOPLASTIC
Increased incidence and severity of renal pelvis urothelial hyperplasia and an increased incidence of renal papillary mineralization and necrosis was found in males of the high dose group. The observed histopathological effects in males were slight to moderate. In females no histopathological changes were observed.

HISTOPATHOLOGY: NEOPLASTIC
Neoplastic histopathological changes were not found.

Dose descriptor:

NOAEL

Effect level:

249 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: Effect type: toxicity

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

249 mg/kg bw/day

Study duration:

chronic

Species:

rat

System:

urinary

Organ:

kidney

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the assessment of all available data classification in accordance with EU Directive 67/548/EEC (DSD) and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008 is not warranted

Additional information

Two carcinogenicity (104 weeks) OECD 451 and GLP compliant studies are available. A drinking water study was conducted with F344/DuCrlCrlj rats. 50 rats per sex were exposed to nominal concentration of 0, 2500, 5000, and 10000 mg/L. Analytical concentrations in drinking water were determined with HPLC. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 124, 249, and 510 mg/kg/day in males and 191, 380, and 795 mg/kg/day in females. Mortality and clinical signs were investigated. Food intake, water intake and body weight were determined weekly during the first 13 weeks followed by measurements once every 4 weeks until study termination. After 104 weeks urinalysis, haematology, blood chemistry, gross pathology, organ weights and histopathology (both non-neoplastic and neoplastic lesions) were examined. No neoplastic lesions were found in either sex. Additionally, a drinking water study with B6D2F1/Crlj mice was conducted. The study design and examination/observations were similar to the study in rats. However, the dose levels differed and were 0, 5000, 10000 and 20000 mg/L. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 468, 898, and 1701 mg/kg/day for males and 586, 1072, and 2058 mg/kg/day for females. After 104 weeks repeated dosing, no treatment related neoplastic lesions were found in either sex. Based on both rat and mice studies, there is no evidence of carcinogenic activity of the test substance in male or female rat and mice.

For DNEL derivation, the benchmark dose method was used to derive a BMDL10 on basis of repeated dose toxicity studies. BMDL10 = 369 mg/kg bw/day.