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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:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1981

Materials and methods

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

Test material

Constituent 1
Reference substance name:
Phenylethyl alcohol
IUPAC Name:
Phenylethyl alcohol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: The animasl used were Charles River CD albino rats purchased from Charles River Breeding Laboratories, Wilmington, MA.
- Age at study initiation: approximately 7-9 wk of age
- Weight at study initiation: 185-316 g (males) and 158-257 g (female)
- Housing: Animals were housed in wire- mesh - bottomed stainless- steel cages. at temperature of 21,-22 °C and humidity of 50-55 % with a
- Diet (e.g. ad libitum): Powered Purina Rodent Chow 5001
- Water (e.g. ad libitum): Fresh tap water
- Acclimation period: During 3 weeks acclimatation period, rats were randomly assigned to four treatment groups and a control group.

ENVIRONMENTAL CONDITIONS
- Temperature: 21-22 °C
- Humidity: 50-55 %
- Photoperiod (hrs dark / hrs light): 12-hr light/darl cycle.

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: application by inuction to the shaved dorsa
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.25, 0.50, 1.00, 2.00 ml/kg body weight


Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, 0.50, 1.00, 2.00 ml/kg/ bw
Basis:
other: dose applied, equivalent to 255, 510, 1020, 2040 mg/kg bw/d (based on d = 1.0202 g/cm3)
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. Four groups of animals were treated with 0.25, 0.50, 1 and 2 ml/kg body weight. The Fifth group (30 males and 30 females) was maintained unshaved and untreated and was used as control. The rats were treated once per day for 90 consecutive days.
Positive control:
15 males and 15 females

Examinations

Observations and examinations performed and frequency:
Observation:
Animals were observed daily for change in appearance and behaviour. Body weight and food consumption were measured weekly. Funduscopic and biomicroscopic examinations were performed on the eyes of all animals. Blood samples were collected as week 13 and examinations included: hemoglobin, haematocrit, erythrocyt count, total and differential leucocyte counts. Biochemical analysis 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 and analysed as well.

Sacrifice and pathology:
The animals were sacrificed using carbon- dioxide asphyxiation after 90 days of treatment
GROSS PATHOLOGY and HISTOPATHOLOGY: Yes- 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 muscles from all control rats and those exposed to the highest dose level were examinated. Sternal bonemarrow smears from the small groups as well.
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
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
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: No abnormalities and no deaths

BODY WEIGHT AND WEIGHT GAIN: The body weight of male and female rats treated with 1 and 2 ml/kg bw decreased statistically from the control starting from week 1.

FOOD CONSUMPTION: No difference in food consumption by the groups

OPHTHALMOSCOPIC EXAMINATION: No changes in either the fundus or anterior segments.

HAEMATOLOGY: Significant decrease in haemoglobin concentration and white blood cell count at wk 6 and 13 among male rats dosed with 2.00 ml/kg/bw.

BLOOD and URINALYSIS CHEMISTRY: Blood and urinary analyses were not significantly affected among the groups at any of the concentrations tested.

ORGAN WEIGHTS: significant increase in relative organ weight of brain, kidney and gonads occurred at 2.00 ml/kg. Relative liver weights were increased in all female dose groups. Absolute and relative liver weights were decreased in males at 1.00 ml/kg/bw (unaffected at 2.00 ml/kg/bw , hence toxicological relevance doubtful).

GROSS PATHOLOGY: Non-dose-related changes in lung and stomach
Lung: congestion and/or focal areas of colour change on the pleural surface of one or more lobes.
Stomach: petechiae on the gastric mucosa.
Absence of dose-relationship suggests findings are of doubtful toxicological relevance

MICROSCOPIC EXAMINATION: Animals treated with 2.00 ml/kg/bw did not show any treatment-related effects.
Incidental findings were found in the liver, myocardium, kidney such as focal aggregates of mononuclear cells. In the lungs, accumulations of lymphocytes about small vassels and air passages, with some extension into intralveolar septa, and mild proliferation of alveolar macrophages.

OTHER FINDINGS: Mild hyperplasia of hepatocytes was observed in 3 controls and 1 treated animal. Moreover, a spontaneus liposarcoma was seen in the mesentery of 1 control animal.

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: Based on decreased body weight and haematological/organ weight effects at higher treatment levels.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the bases of the results of the 90-days toxicity study on Phenyl ethyl alcohol, the no-effect level (NOAEL) is considered to be 0.50 ml/kg/day.
Executive summary:

In this study, the test material Phenyl ethyl alcohol was administrated percutaneously to 15 males and 15 females Sprague-Dawley rats. The dose levels of 0.25, 0.50, 1.00, 2.00 ml/kg/bw were administered once per day for 90 consecutively days. The results showed no abnormalities and no deaths during the treatment period. The body weight of female and male rats treated with dose of 1.00 or 2.00 ml/kg/bw decreased significantly. Hematologic results showed a decrease in haemoglobin concentration and white blood cell count at wk 6 and 13 among male rats dosed with 2.00 ml/kg/bw. On the contrary, ophthalmoscopic examination, blood and urinary analysis did nor show any significant changes. Brain, kidney and gonads weight of rats of both sexes treated with 2.00 ml/kg were significantly increased, as well as the relative liver weight at all doses among females. Both absolute and relative weight were decreased in males at dose level of 1.00 ml/kg/bw. This was not confirmed at 2.00 ml/kg/bw and therefore it is not considered of toxicological relevance. Microscopic examinations on animals treated with 2.00 ml/kg/bw showed no treatment-related differences between the two groups.Incidental findings were found in the liver, myocardium, kidney such as focal aggregates of mononuclear cells. In the lungs, accumulations of lymphocytes about small vassels and air passages, with some extension into intralveolar septa, and mild proliferation of alveolar macrophages. Finally, mild hyperplasia of hepatocytes was observed in 3 controls and 1 treated animal and a spontaneus liposarcoma was seen in the mesentery of 1 control animal.