Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
A 90-day study of phenylethyl alcohol in the rat
Author:
Owston, E., Lough, R., Opdyke, D.L.,
Year:
1981
Bibliographic source:
Food and Cosmetics Toxicology 19 (6), 713–715

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
Phenylethyl alcohol - 99.9% purity, supplied by the Research Institute for Fragrance Materials, Inc

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
Animals - The animals used were Charles River CD albino rats purchased from Charles River Breeding Laboratories, Wilmington, MA. On day one of treatment, the rats were 7-9 weeks old and weighed 185-316g (males) and 158-257g (females).
Environmental conditions - The animals were housed in wire-mesh-bottomed stainless-steel cages in rooms maintained at 21 +/- 2°C and 50 +/- 5% relative humidity with a 12-hour light/dark cycle.

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
The test material was applied by inunction to the shaved dorsa of the rats. The animals were treated with 0.25, 0.50, 1.00 and 2.00 ml/kg body weight.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Dose concentrations: 0.25, 0.50, 1.00 and 2.00 ml/kg body weight.
Equivalent to: 255, 510, 1020, 2040 mg/kg bw based on density of 1.0202
No. of animals per sex per dose:
15 males and 15 females
Control animals:
yes
Details on study design:
The test material was applied by inunction to the shaved dorsa of the rats. The four treatment groups each consisted of 15 males and 15 females and were treated with 0.25, 0.50, 1.00 and 2.00 ml/kg body weight respectively. A fifth group of 30 males and 30 females (cage control) was maintained unshaven and untreated as a reference.

Examinations

Observations and examinations performed and frequency:
Animals were observed daily for change in appearance and behaviour. Body weights and food consumption were measured weekly. Funduscopic and biomicroscopic examinations were performed on the eyes of all animals before treatment and at week 13. Blood samples were collected at weeks 6 and 13 from 5 animals of each sex from each group and the following determinations made: haemoglobin, haematocrit, erythrocyte count and total and differential leucocyte counts. Biochemical analysis on the same samples included: fasting serum glucose, blood urea nitrogen, alkaline phosphates, glucose, blood urea nitrogen, alkaline phosphatase, glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. Urine samples were collected at week 6 and 13 and volume, colour, transparency, odour, specific gravity, pH, bilirubin, protein, glucose, ketones and occult blood and for a microscopic examination of the urinary sediment.
Sacrifice and pathology:
The rats were asphyxiated by carbon dioxide after 90 days. Autopsies were carried out on and the brain, kidneys, liver and gonads were dissected free of fat and weighed. Microscopic examination was carried out on the adrenals, brain, heart, kidneys, liver, lung and bronchi, mesenteric lymph node, pituitary, sternum, spinal cord, testes with epididymides, ovaries, spleen, urinary bladder and nerve with muscle from all control rats and those exposed to the highest dose. Sternal bone-marrow smears from the same groups were also examined.
Statistics:
Differences between the control group and each of the treated groups were tested for statistical significance using Student's t test (P < 0.05).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight among animals treated with 1.00 or 2.00 ml/kg bw were significantly decreased after 1 week of treatment and remained so for the duration of the experiment.
The mean body-weight gains of both sexes were depressed among the treated animals in a dose-dependent fashion and the decreases were statistically significant at 1.00 and 2.00 ml/kg.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There was a significant decrease in haemoglobin concentration and white blood cell count among male rats dosed with 2.00 ml/kg.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Significant increases in the relative weights of the brain, kidneys and gonads occurred among rats of both sexes given the dose 2.00 ml/kg.
Relative liver weights were increased at all doses among the females and both absolute and relative liver weights were decreased among the males given 1.00 ml/kg. This was not confirmed at 2.00 ml/kg and thus was not considered to be toxicologically significant.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Gross pathological changes in the lungs and stomach of animals killed after 90 days of treatment were seen in all groups including the controls. Petechiae on the gastric mucosa were frequently observed in all groups. The incidence of these findings was not related to dosage.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
510 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: decreased body weight and organ effects at higher treatment levels.

Applicant's summary and conclusion

Conclusions:
The no-effect level for 2-phenylethanol is 0.5 ml/kg/day (or 510 mg/kg bw/day).
Executive summary:

2 -phenylethanol was applied by inunction to the shaved dorsa of groups of 15 male and 15 female rats.  The doses were 0.25, 0.50, 1.00 and 2.00 ml/kg body weight daily for 90 days. There were no abnormalities or mortalities during the treatment period. The body weights of the rats treated with 1.00 and 2.00 ml/kg bw decreased significantly. There was a significant decrease in haemoglobin concentration and white blood cell count among male rats dosed with 2.00 ml/kg. Significant increases in the relative weights of the brain, kidneys and gonads occurred among rats of both sexes given the dose 2.00 ml/kg.  

Relative liver weights were increased at all doses among the females and both absolute and relative liver weights were decreased among the males given 1.00 ml/kg.  This was not confirmed at 2.00 ml/kg and thus was not considered to be toxicologically significant. Gross pathological changes in the lungs and stomach of animals killed after 90 days of treatment were seen in all groups including the controls. Petechiae on the gastric mucosa were frequently observed in all groups, the incidence of these findings was not related to dosage.