Phenethyl phenylacetate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from publication.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Subacute and Chronic Toxicity studied in rodents.

Author:

HAGAN et al.

Year:

1967

Bibliographic source:

Fd Cosmet. Toxicol

Reference 2

Reference Type:

publication

Title:

Flavoring substance evaluation by the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food

Author:

EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food

Year:

2005

Bibliographic source:

EFSA Journal, 2005

Reference 3

Reference Type:

publication

Title:

Monograph on fragrance raw materials

Author:

D.L.J Opdyke

Year:

1975

Bibliographic source:

Food and Cosmetics Toxicology ,1975

Reference 4

Reference Type:

publication

Title:

The FEMA GRAS assessment of test chemical

Author:

Adams et al.

Year:

2005

Bibliographic source:

Food and Chemical Toxicology

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

To evaluate the toxic potential of test chemical in male and female rats by oral feed for 17 weeks.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenethyl phenylacetate

EC Number:

203-013-1

EC Name:

Phenethyl phenylacetate

Cas Number:

102-20-5

Molecular formula:

C16H16O2

IUPAC Name:

2-phenylethyl phenylacetate

Details on test material:

- Name of test material (as cited in study report): phenethyl phenylacetate
- Substance type: organic
- Physical state: Liquid

Test animals

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: The animals were housed individually in wire cages
- Diet (e.g. ad libitum): Rodent diet ad libitum
- Water (e.g. ad libitum): water ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Rodent diet

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency):The test chemical was fed in the diet and fresh diets were made and distributed weekly.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Not specified.

Duration of treatment / exposure:

17 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
1000, 2500 and 10000 ppm, corresponding to an average daily intake of 0, 50, 250 or 500 mg/kg bw
Basis:
no data

No. of animals per sex per dose:

Total number of animals 80
0 mg/kg/day-10 male and 10 female
50 mg/kg/day-10 male and 10 female
250 mg/kg/day-10 male and 10 female
500 mg/kg/day-10 male and 10 female

Control animals:

yes, plain diet

Details on study design:

no data available

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Haematological examinations were made at termination of the subacute studies
- Parameters checked in table [No.?] were examined. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified


OTHER: The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes , At the termination of the experiments the rats were sacrificed and exsanguinated.

HISTOPATHOLOGY: Yes , The tissues of all the rats were examined macroscopically at the time of sacrifice. These organs, the remaining abdominal and
thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological
examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin.

Other examinations:

Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted

Statistics:

Not specified

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.

Mortality:

no mortality observed

Description (incidence):

No mortality were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Weekly measurement of body weight showed no significant difference between test and control animals.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Weekly measurement of food intake showed no significant difference between test and control animals.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

At termination, haematological examination revealed no effects due to treatment. No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

At necropsy, no difference between test and control animals in the weights of major organs was reported.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Gross examination of tissues from all animals revealed no remarkable changes, and histological examination of three to four animals of each sex at the high dose and from the control group revealed no treatment-related lesions.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

At termination, hematological examinations revealed no effects due to administration of the test chemical. At necropsy, no differences were reported in major organ weights between test and control animals. Gross examination of tissue of all animals was unremarkable and histopathological examination of six-eight animals, equally represented by gender, for the high-dose group and the control group revealed no treatment-related lesions. Hence, the highest dose tested i.e 500 mg/kg/day can be considered as the NOAEL.

Executive summary:

Repeated dose oral study for test chemical was assessed for its possible toxic potential. Groups of 10 male and 10 female Osbourne-Mendel rats were provided test chemical mixed in the diet at concentrations of 0, 1000, 2500 or 10,000 ppm which corresponding to an average daily intakes of 0, 50, 250, or 500 mg/kg bw per for 17 weeks. The animal’s weight, food intake and general condition were recorded every week. Haematological examinations were made at termination of the subacute studies. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10% buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Measurement of body weight and food intake recorded weekly showed no significant difference between test and control animals at any intake level. At termination, hematological examinations revealed no effects due to administration of the test chemical. At necropsy, no differences were reported in major organ weights between test and control animals. Gross examination of tissue of all animals was unremarkable and histopathological examination of six-eight animals, equally represented by gender, for the high-dose group and the control group revealed no treatment-related lesions. Hence, the highest dose tested i.e 500 mg/kg/day can be considered as the NOAEL.