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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
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 Toxicity Study Of Phenylethyl Alcohol In The Rat
Author:
Owston and Lough
Year:
1981
Bibliographic source:
Fd Cosmet. Toxicol. Vol. 19. pp. 713 to 715.

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
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-methyl-4-phenylbutan-2-ol
EC Number:
203-074-4
EC Name:
2-methyl-4-phenylbutan-2-ol
Cas Number:
103-05-9
Molecular formula:
C11H16O
IUPAC Name:
2-methyl-4-phenylbutan-2-ol
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Sourceof test material: Research Institute for Fragrance Materials
- Purity: 99.9%

Test animals

Species:
rat
Strain:
other: Charles River CD albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: approximately 7-9 weeks
- Weight at study initiation: 185-316 g (males) and 158-257 g (females)
- Housing: . Animals were housed in wire-mesh-bottomed stainless-steel cages
- Diet: Powdered Purina Rodent Chow 5001 ad libitum
- Water: fresh municipal tapwater ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 50 ± 5%
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: shaved dorsa

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0, 0.25, 0.5, 1.0, or 2.0 mL/kg (equivalent to 0, 250, 500, 1000, or 2000 mg/kg bw/day)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0.25 other: mL/kg/day
Remarks:
Equivalent to 250 mg/kg bw/day
Dose / conc.:
0.5 other: mL/kg/day
Remarks:
Equivalent to 500 mg/kg bw/day
Dose / conc.:
1 other: mL/kg/day
Remarks:
Equivalent to 1000 mg/kg bw/day
Dose / conc.:
2 other: mL/kg/day
Remarks:
Equivalent to 2000 mg/kg bw/day
No. of animals per sex per dose:
15 males
15 females
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were observed daily for changes in appearance and/or behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured weekly.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (measured weekly)

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Funduscopic and biomicroscopic examinations were performed on the eyes of all animalsbefore treatment and at wk 13. one drop of a 1% atropine sulphate solution being instilled into each eye to dilate the pupil prior to examination

HAEMATOLOGY: Yes
At wk 6 and 13 blood samples collected from the orbital sinus of five animals of each sex from each group were subjected to the following determinations: haemoglobin. haematocrit. erythrocyte count and total and differential leucocyte counts (Coulter Counter ZBI-6 or manual methods).

CLINICAL CHEMISTRY:
Biochemical analyses, performed on the same samples, comprised fasting serum glucose. blood-urea nitrogen. alkaline phosphatase, glutamic- oxalacetic transaminase and glutamic-pyruvic transaminase (automated methods, Abbott Diagnostics).

URINALYSIS: Yes / No / No data
Urine samples were collected over a 16-hr period at wk 6 and 13 for the recording of volume, colour, transparency, odour, specific gravity, ph. bilirubin, protein, glucose, ketones and occult blood and for a microscopic examination of the urinary sediment (semi-automated or manual methods).
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Autopsieswere carried out and the brain, kidneys, liver and gonads were dissected free of fat and weighed. All tissues were preserved in 10”” neutral buffered formalin.

HISTOPATHOLOGY: Yes. Microscopic examination was performed by a veterinary pathologist on representative sections of paraffin-embedded skin (treated and untreated). 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 given the highest dose level. These sections were stained with haematoxylin-eosin. Sternal bone marrow smears from the same groups were stained with May-Griinwald-Giemsa and examined by a haematopathologist.
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) when the nature of the data permitted.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Clinical examinations did not reveal abnormalities or differences among the groups.
Dermal irritation:
not examined
Mortality:
no mortality observed
Description (incidence):
No deaths occurred during the treatment period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Among animals treated with 1.00 or 200 ml/kg, body weights were decreased significantly after 1 wk of treatment and remained so for the duration of the experiment. After 90 days, the mean body-weight gains of rats treated with 0, 0.25. 0.50, 1.00 or 200 ml/kg were 260. 249, 248, 218 and 218 g, respectively, for the males and 98, 93, 87. 78 and 70g for the females (Table 1). The mean body-weight gains of both sexes were depressed among 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
Description (incidence and severity):
There were no differences in the amounts of food consumed by the groups; thus, treated animals consumed a significantly greater amount of food relative to the gain in body weight than did the control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmological examination revealed no changes in either the fundus or anterior segment.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Haematological results indicated a significant decrease in haemoglobin concentration and white blood cell count at wk 6 and 13 among male rats dosed with 2.00 ml/kg.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Blood biochemistry was not significantly affected among the groups at any of the assessment periods.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinary analyses was not significantly affected among the groups at any of the assessment periods.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-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 200 ml/kg. Relative liver weights were increased at all doses among the females and both absolute and relative liver weights were de creased among the males given 1.00 ml/kg. The elevations in relative organ weights while absolute values remained unchanged were related to decreases in body weight, particularly among animals dosed with 1.00 or 2.00 ml/kg. The decrease in both absolute and relative liver weights in males treated with 1.00 ml/kg 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. The lung findings consisted of congestion and/or focal areas of colour change on the pleural surface of one or more lobes. 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:
effects observed, non-treatment-related
Description (incidence and severity):
Microscopic examination of tissues taken from the control and high-dose (2.00 ml/kg) animals did not show any treatment-related differences between the two groups. Various incidental findings, such as focal aggregates of mononuclear cells within the liver, myocardium and kidney, were found. Pulmonary changes consisted of accumulations of lymphocytes about blood vessels and air passages, with some exten- sion into interalveolar septa, and mild proliferation of alveolar macrophages. Mild hyperplasia of hepatocytes (hyperplastic nodule) was seen in three control and one treated (2.00 ml/kg) animal, and a spontaneous liposarcoma was seen in the mesentery of one control rat.
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a 90 day sub-chronic toxicity study in Charles River CD albino rats, the NOEL value (males/females) for PEA was 500 mg/kg bw/day based on the changes in body weights.
Executive summary:

In a 90 day sub-chronic toxicity study (Owston and Lough, 1981), PEA (99.9%) was administered to four groups of Charles River CD albino rats (15 animals/sex/group) dermally at dose levels of 0, 0.25, 0.5, 1.0, or 2.0 mL/kg (equivalent to 0, 250, 500, 1000, or 2000 mg/kg bw/day), 7 days per week, for 90 days. No deaths occurred during the treatment period and clinical examinations did not reveal abnormalities or differences among the groups. Among animals treated with 1000 and 2000 mg/kg bw/day body weights were decreased significantly after 1 wk of treatment and remained so for the duration of the experiment. After 90 days, the mean body-weight gains of rats treated with 0, 250, 500, 1000, or 2000 mg/kg bw/day were 260, 249, 248, 218 and 218 g, respectively, for the males and 98, 93, 87, 78 and 70g for the females. The mean body-weight gains of both sexes were depressed among treated animals in a dose-dependent fashion and the decreases were statistically significant at 1000 and 2000 mg/kg bw/day. There were no differences in the amounts of food consumed by the groups; thus, treated animals consumed a significantly greater amount of food relative to the gain in body weight than did the control animals.

Ophthalmological examination revealed no changes in either the fundus or anterior segment. Haematological results indicated a significant decrease in haemoglobin concentration and white blood cell count at week 6 and 13 among male rats dosed with 2000 mg/kg bw/day. Blood biochemistry or urinary analyses was not significantly affected among the groups at any of the assessment periods. Significant increases in the relative weights of the brain, kidneys and gonads occurred among rats of both sexes given 2000 mg/kg bw/day. Relative liver weights were increased at all doses among the females and both absolute and relative liver weights were decreased among the males given 1000 mg/kg bw/day. The elevations in relative organ weights while absolute values remained unchanged were related to decreases in body weight, particularly among animals dosed with 1000 mg/kg bw/day or 2000 mg/kg bw/day. The decrease in both absolute and relative liver weights in males treated with 1000 mg/kg bw/day was not confirmed at 2000 mg/kg bw/day 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. The lung findings consisted of congestion and/or focal areas of colour change on the pleural surface of one or more lobes. Petechiae on the gastric mucosa were frequently observed in all groups. The incidence of these findings was not related to dosage. Microscopic examination of tissues taken from the control and high-dose (2000 mg/kg bw/day) animals did not show any treatment-related differences between the two groups. Various incidental findings, such as focal aggregates of mononuclear cells within the liver, myocardium and kidney, were found. Pulmonary changes consisted of accumulations of lymphocytes about small blood vessels and air passages, with some extension into interalveolar septa, and mild proliferation of alveolar macrophages. Mild hyperplasia of hepatocytes (hyperplastic nodule) was seen in three control and one treated (2000 mg/kg bw/day) animal, and a spontaneous liposarcoma was seen in the mesentery of one control rat. The NOEL value for males and females was 500 mg/kg bw/day based on the changes in body weights.

This dermal toxicity study in the rat is acceptable and satisfies the guideline requirement for a repeat-dose dermal toxicity study (OECD 411).