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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Hemolytic Activity of Ethylene Glycol Phenyl Ether (EGPE) in Rabbits
Author:
Breslin WJ, Phillips JE, Lomax LG, Bartels MJ, Dittenber DA, Calhoun LL, Miller RR.
Year:
1991
Bibliographic source:
FUNDAMENTAL AND APPLIED TOXICOLOGY 17, 466-48 1 (1991)

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Subchronic dermal toxicity of 2-phenoxy ethanol was assessed in New Zealand White Rabbit in 90 days study period
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-phenoxyethanol
EC Number:
204-589-7
EC Name:
2-phenoxyethanol
Cas Number:
122-99-6
Molecular formula:
C8H10O2
IUPAC Name:
1-hydroxy-2-phenoxyethane
Constituent 2
Reference substance name:
2-phenoxy ethanol
IUPAC Name:
2-phenoxy ethanol
Test material form:
other: Liquid
Details on test material:
- Name of test material : 2-phenoxyethanol
- Molecular formula : C8H10O2
- Molecular weight : 138.17
- Substance type : Organic
- Physical state : Liquid
- Impurities :1% (no data available regarding identity of impurities)

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: Hazleton-Dutchland, Denver, PA
- Age at study initiation: 5 months of age
- Housing: individually (in cages with wire floors)
- Diet (e.g. ad libitum): Certified Laboratory Rabbit Chow
- Water (e.g. ad libitum): Tap water (ad libitum)
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 deg C
- Humidity (%): relative humidity at 50%
- Photoperiod (hrs dark / hrs light): 12 hr light: 12 hr dark photocycle


















Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Details on Dermal exposure
Dosing volume: approximately 0.05 to 0.50 ml/kg/day

2-phenoxyethanol was uniformly spread over a clipped area (approximately 10 X 15 cm) using a syringe and Hunt-tipped needle. The application site was reclipped as required during the study to keep it free of hair. An occlusive wrap of absorbent gauze and nonabsorbent cotton was placed over the application area and was held in place using an elastic jacket. The wraps and jackets were removed approximately 6 hr after each dose was applied. The backs of the rabbits were not wiped since no appreciable amount of test material was apparent at the site of application after the 6-hr exposure period.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days (13 weeks)
Frequency of treatment:
5 days/week (6 hr/day)
Doses / concentrations
Remarks:
Doses / Concentrations:
0,50, 150,or 500 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Ten New Zealand White rabbits/sex/group were treated with 0, 50, 150, or 500 mg/kg/day of undiluted 2-phenoxyethanol for 6 hr/day, 5 days/week, for 13 weeks by dermal route. Dosing volume was approximately 0.05 to 0.50 ml/kg/day and was adjusted weekly based upon body weight Control rabbits received 0.5 ml/kg/day distilled water.

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
BODY WEIGHT: Yes
Body weight observed

HAEMATOLOGY: Yes
Blood samples (approximately 7 ml) for hematology determinations were obtained from the auricular artery of all rabbits approximately 1 week prior to dosing and after 4 and 13 weeks of treatment. Samples for hematologic determinations were collected using vacuum tubes, and mixed with potassium EDTA anticoagulant. RBC, WBC, and PLAT counts, HGB concentration, PCV, and RBC indices (MCV, MCH, MCHQ were determined on all samples. Differential leukocyte and reticulocytes (RETICS) counts and RBC morphologic determinations were conducted on samples from all control and high dose group rabbits by direct microscopic examination of stained smears after 13 weeks of treatment only.


CLINICAL CHEMISTRY: Yes
Blood samples (approximately 7 ml) for clinical chemistry determinations were obtained from the auricular artery of all rabbits approximately 1 week prior to dosing and after 4 and 13 weeks of treatment.
Blood samples for clinical chemistry determinations were allowed to clot at 0-5 °C and serum was harvested by centrifugation. Alanine aminotransferase activity, aspartate aminotransferase activity, urea nitrogen, alkaline phosphatase activity, glucose, total protein, albumin, globulin, and total bilirubin were determined on all samples.

ORGAN WEIGHT: Yes
On the day following the last dermal application of 2-phenoxyethanol each rabbit was euthanatized with CO2, weighed and examined for gross pathological alterations. Brain, heart, liver, kidneys, and testes were weighed and relative organ weights (g/100 g body weight) were calculated.
Sacrifice and pathology:
Sacrifice and pathology
HISTOPATHOLOGY: Yes
Sample of all organ systems and tissues were collected from each rabbit at necropsy and preserved in neutral, phosphate-buffered 10% formalin. All tissues collected from control and high dose animals were processed by conventional histological techniques, stained with hematoxylin and eosin and evaluated by light microscopy.
Statistics:
Descriptive statistics (means and standard deviation) were evaluated for body weight, RBC indices, RBC Met-HGB, RBC GSH, RBC fragility, WBC differential count, serum EGPE, and PAA residue

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No overt signs of systemic toxicity (including hemoglobinuria) or early mortality of treated rabbits were noted over the 13-week dosing period.
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Description (incidence):
No overt signs of systemic toxicity (including hemoglobinuria) or early mortality of treated rabbits were noted over the 13-week dosing period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects observed on Body weight
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No effects observed on Hematology
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effects observed on clinical chemistry
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No effects observed on organ weights
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No gross or microscopic changes attributable to EGPE exposure were observed in any tissue examined.
Histopathological findings: neoplastic:
not examined
Details on results:
Other effects:
The only potentially treatment-related effect was the sporadic observation of erythema and very slight-to-slight scaling of the skin at the site of test material application in male and female rabbits exposed to 500 mg EGPE/kg/day. However, as these effects were not associated with gross or histological changes in the skin they were not considered to be of toxicologic significance.

Effect levels

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed on Mortality, Body weight, organ weight, Clinical chemistry, hematology, histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL of EGPE (i.e. 2-phenoxy ethanol) on New Zealand White rabbits in a 90 days dermal exposure study was considered to be 500 mg/kg/day.
Executive summary:

In conclusion, dermal exposure of rabbits to high doses (500 mg/kg/day) EGPE(i.e.2-phenoxy ethanol)does not result in systemic toxicity. Other effects observed were not considered to be of toxicological significance.

Therefore, the NOAEL of EGPE was considered to be 500 mg/kg/day when administered dermally.