3-methyl-5-phenylpentanol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study provides sufficient details on material and methods, and also a detailed description of the results, but only body weight data are presented. The study appears to have been conducted in line with good scientific principles and is in basic compliance with the standardised OECD guideline. The study demonstrates a clear dose-related reduction of body weight in non-pregnant animals, as recorded in the developmental and reproductive toxicity studies, and changes in liver weights akin to the adaptive responses noted in the subacute oral studies performed with 3-methyl-5-phenylpentanal (the aldehyde of 3-methyl-5-phenylpentanol).

Data source

Reference

Reference Type:

publication

Title:

A 90-day toxicity study of phenylethyl alcohol in the rat.

Author:

Owston E, Lough R & Opdyke DL

Year:

1981

Bibliographic source:

Food and Cosmetics Toxicology. 19 (6): 713–715.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

no

Principles of method if other than guideline:

Phenethyl alcohol was administered percutaneously to groups of Sprague-Dawley rats (15 rats/sex/dose) at 0, 0.25, 0.50, 1.00 or 2.00 mL/kg bw/day for 90 days. Control animals were not shaved and did not receive any treatment. Animals were observed for clinical symptoms of toxicity and behavioural abnormalities. Body weights and food consumption were examined weekly. Ophthalmic examinations were performed on the eyes of all animals before treatment and at week 13. Blood samples were collected haematological parameters and clinical chemistry assessment.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-phenylethanol

EC Number:

200-456-2

EC Name:

2-phenylethanol

Cas Number:

60-12-8

IUPAC Name:

2-phenylethanol

Test material form:

not specified

Details on test material:

- Name of test material: Phenethyl alcohol
- Analytical purity: 99.9 %

Test animals

Species:

rat

Strain:

other: Crl:CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7-9 weeks
- Weight at study initiation: 185-316 g males, 158-257 g females
- Housing: Wire-mesh bottomed stainless steel cages
- Diet: ad libitum
- Water: fresh municipal tap water ad libitum
- Acclimation period: 3 weeks

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

Administration / exposure

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: Dorsa (shaved)

TEST MATERIAL
- Amount(s) applied: 0.25, 0.50, 1.00 and 2.00 mL/kg bw/day equivalent to 250, 500, 1000 and 2000 mg/kg bw/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: no, the test material was applied by inunction

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

- 90 days

Frequency of treatment:

- Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0.25, 0.50, 1.00 and 2.00 mL/kg bw/day equivalent to 250, 500, 1000 and 2000 mg/kg bw/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

- 15 animals per sex per dose in the treated groups, 30 animals per sex per dose in the cage control (untreated and unshaved).

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: The basis of this study was designed around previously performed acute and subacute studies.

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

DERMAL IRRITATION: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly

FOOD EFFICIENCY: Food efficiency was not calculated, but was considered relative to the quantities of food consumed vs. the differences in changes in bodyweight compared between the control and treated groups.

OPHTHALMOSCOPIC EXAMINATION: Yes, funduscopic and biomicroscopic
- Time schedule for examinations: At the beginning of the study and again at week 13
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 6 and 13 (from the orbital sinus)
- How many animals: Five animals per sex per dose
- Animals fasted: Yes
- Parameters checked: haemoglobin, haematocrit, erythrocyte count and total and differential leucocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 6 and 13 (from the orbital sinus)
- How many animals: Five animals per sex per dose
- Animals fasted: Yes
- Parameters checked: Fasting serum glucose, blood-urea nitrogen, alkaline phosphatase, glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase

URINALYSIS: Yes
- Time schedule for collection of urine: Week 6 and 13 (collected over a 16 hour period)
- Animals fasted: Yes
- Parameters checked: volume, colour, transparency, odour, specific gravity, pH, bilirubin, protein, glucose, ketones and occult blood. Microscopic examination of the urinary sediment was also performed.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. Autopsies were performed on the brain, kidneys, liver and gonads.
HISTOPATHOLOGY: Yes. Microscopic analysis was performed on skin, 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 the highest dose group. Sternal bone marrow smears were also examined.

Statistics:

- Student's t test with a level of significance of 0.05 (p < 0.05) was used to examine differences between the control group and treated groups.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment related effects.

Dermal irritation:

not specified

Mortality:

no mortality observed

Description (incidence):

No treatment related effects.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1000 and 2000 mg/kg bw/day bodyweights were signficantly depressed from week 1 of dosing, a dose-related pattern was observed.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No treatment related effects.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Reduced in treated animals.

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No treatment related effects.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Significant decrease in haemoglobin concentration and white blood cell count in males dosed with 2000 mg/kg bw/day.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No treatment related effects.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment related effects.

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Significant increases in relative weights of the brain, kidneys and gonads in both sexes at 2000 mg/kg bw/day. Relative liver weights were increased in all treated females. Relative and absolute liver weights were decreased in the 1000 mg/kg bw/day males.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment related effects.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment related effects.

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No deaths or abnormalities observed.

BODY WEIGHT AND WEIGHT GAIN
Bodyweights were significantly depressed in the 1000 and 2000 mg/kg bw/day groups after the first week of treatment and remained so until the end of the study. All treated animals demonstrated a dose related decrease in bodyweights and bodyweight gains.

FOOD CONSUMPTION
Food consumption was not affected during the study.

FOOD EFFICIENCY
There were no differences in the amounts of food consumed by the treated animals, therefore the treated animals consumed a significantly greater amount of food relative to bodyweight gain when compared to controls.

OPHTHALMOSCOPIC EXAMINATION
No effects observed in either the fundus or anterior segment.

HAEMATOLOGY
A significant decrease in haemoglobin concentration and white blood cell count was noted at week 6 and 13 in male rats in the 2000 mg/kg bw/day group.

CLINICAL CHEMISTRY
Not significantly affected.

URINALYSIS
Not significantly affected.

ORGAN WEIGHTS
Significant increases in relative weights of the brain, kidneys and gonads were noted in both sexes at the 2000 mg/kg bw/day dosing level. Relative liver weights were increased in all treated females. In the 1000 mg/kg bw/day males, relative and absolute liver weights were decreased, this was not considered to be treatment related. The unchanged absolute organ weights where increases in the relative organ weights were observed were due to the decreases in bodyweights.

GROSS PATHOLOGY
No treatment related effects were observed.

HISTOPATHOLOGY
No treatment related effects were observed.

Effect levels

Dose descriptor:

NOEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: bodyweights and haematology

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Bodyweights of the animals throughout the dosing period.

Dose (mL/kg bw/day)	Bodyweights (g) at week:
	0	4	8	12
Males
0.00	268 ± 20	410 ± 31	486 ± 40	528 ± 48
0.25	263 ± 24	397 ± 29	472 ± 38	512 ± 40
0.50	274 ± 19	403 ± 34	478 ± 37	522 ± 42
1.00	264 ± 26	383 ± 40*	449 ± 49*	482 ± 56*
2.00	266 ± 22	382 ± 35*	448 ± 40*	484 ± 43*
Females
0.00	208 ± 20	263 ± 26	288 ± 29	306 ± 32
0.25	208 ± 19	261 ± 24	285 ± 30	301 ± 35
0.50	203 ± 20	255 ± 30	279 ± 35	290 ± 38
1.00	198 ± 18	242 ± 20*	264 ± 23*	276 ± 24*
2.00	202 ± 11	246 ± 12*	266 ± 16*	272 ± 16*
Values are means ± SD. Statistical significance measured by Student's t-test (P < 0.05)

Applicant's summary and conclusion

Conclusions:

Dermal administration of phenethyl alcohol to the rat for 90 days under the conditions of the test produced no statistically significant changes in any of the toxicological parameters measured except for bodyweight and haematology (haemoglobin concentration and leucocyte counts) at 1000 and 2000 mg/kg bw/day, the highest no observed effect level in this study was therefore determined to be 500 mg/kg bw/day.

Executive summary:

Phenethyl alcohol was administered percutaneously to groups of Sprague-Dawley rats (15 rats/sex/dose) at 0, 0.25, 0.50, 1.00 or 2.00 mL/kg bw/day for 90 days. Control animals were not shaved and did not receive any treatment. Animals were observed for clinical symptoms of toxicity and behavioural abnormalities. Body weights and food consumption were examined weekly. Ophthalmic examinations were performed on the eyes of all animals before treatment and at week 13. Blood samples were collected for haemoglobin, haematocrit, erythrocyte count and total and differential leukocyte counts at weeks 6 and 13. Biochemical analysis was performed on these same blood samples. Parameters checked included fasting serum glucose, blood-urea nitrogen, alkaline phosphatase, glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. Urine samples were collected over a 16 hour period at week 6 and 13. The rats were sacrificed at week 13 and autopsied. Microscopic examination of tissues was performed.

Weight gain was depressed in both sexes given 1.00 or 2.00 mL/kg bw/day. No effect on food intake was observed. Survival rate was unaffected and ophthalmological examination was unremarkable. Male rats dosed with 2.00 mL/kg bw/day revealed a decrease in haemoglobin concentration and white blood cell count at weeks 6 and 13. Organ weight measurement at all dose levels and microscopic examination of a large variety of tissues did not reveal any treatment related effects. Significant increases in the relative weights of brain, kidneys and gonads occurred in the 2.00 mL/kg bw/day, and were related to the reduced body weights. Relative liver weights were increased at all doses among the females and both absolute and relative liver weights were decreased in males given 1.00 mL/kg bw/day. The decrease in liver weights noted in the males at 1.00 mL/kg bw/day was not observed in the 2.00 mL/kg bw/day group and was not considered to be toxicological significant. The NOEL was determined to be 0.50 mL/kg bw/day.