1-phenylethyl acetate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was performed in line with good scientific principles to a method comparable to current standardised guidelines. A high level of detail was included in both the methods and the results.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1974

Report date:

1974

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-phenylethyl acetate

EC Number:

202-288-5

EC Name:

1-phenylethyl acetate

Cas Number:

93-92-5

Molecular formula:

C10H12O2

IUPAC Name:

1-phenylethyl acetate

Specific details on test material used for the study:

Name of test material: 1-phenylethyl acetate- Name of test material (as cited in study report): Methylphenylcarbinyl acetate- Physical state: colourless liquid- Analytical purity: 98 %- Specific gravity (25/25 °C): 1.023-1.026- Refractive index: 1.494-1.496

Test animals

Species:

rat

Strain:

other: CFE

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Weight at study initiation: 82-115 g males, 68-104 g females- Housing: Five per cage- Diet: ad libitum- Water: ad libitumENVIRONMENTAL CONDITIONS- Temperature (°C): 21 ± 1 °C- Humidity (%): 50-60 %

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Once a day, seven days a week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

150 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

15 males and 15 females per group dosed for the entire 13 weeks, additionally, five rats of each sex were dosed with the 0, 50 or 150 mg/kg bw/day for 2 or 6 weeks.

Control animals:

yes, concurrent vehicle

Positive control:

NA

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: YesBODY WEIGHT: Yes- Time schedule for examinations: Recorded weeklyFOOD CONSUMPTION: Recorded 24 hours prior to weighing- Food consumption for each animal determined and mean daily diet consumption calculated as g food/rat/day: Yes WATER CONSUMPTION: Yes- Time schedule for examinations: Recorded 24 hours prior to weighingHAEMATOLOGY: Yes, at the end of each exposure period, animals were scarified by exsanguination under barbiturate anaesthesia- Time schedule for collection of blood: Blood was collected from the aorta at sacrifice- Animals fasted: Yes, 24 hours- Parameters checked: Haemoglobin, packed cell volume, red blood cells, reticulocytes, neutrophils, eosinophils, lymphocytes and monocytesCLINICAL CHEMISTRY: Yes, at the end of each exposure period, animals were scarified by exsanguination under barbiturate anaesthesia- Time schedule for collection of blood: Blood was collected from the aorta at sacrifice- Animals fasted: Yes, 24 hours- Parameters checked: Urea, glucose and activities of glutamic—oxalacetic transaminase, glutamic-pyruvic transaminase and lactic dehydrogenaseURINALYSIS: Yes- Time schedule for collection of urine: During the final week of treatment.- Parameters checked: Appearance, microscopic constituents and content of glucose, ketones, bile salts and blood were examined. A renal concentration test was also performed. At week 6 and 13, the specific gravity and volume of the urine produced during a 6 hour period of water deprivations, during a 2 hour period following a water load of 25 mL/kg and from 16-20 hours after the water load. At week 2, these measurements were only made during a 6 hour deprivation period. A count of the number of cells in in the urine was carried out with the 6 hour urine sample.

Sacrifice and pathology:

GROSS PATHOLOGY: YesThe following were weighed and examined grossly for macroscopic alterations: brain, pituitary, thyroid, heart, liver, stomach, small intestine, caecum, spleen, kidneys, adrenal glands and gonads.HISTOPATHOLOGY: Yes, the aforementioned tissues that underwent macroscopic examination were also prepared for microscopic examination along with samples of salivary gland, trachea, aorta, lung, lymph nodes, urinary bladder, colon, rectum, pancreas, uterus and skeletal muscle.

Statistics:

Effects were assessed for statistical significance

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption was slightly increased in males treated with 150 mg/kg/day.

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

Water consumption was slightly increased in males treated with 150 mg/kg/day.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Description (incidence and severity):

Cell excretion was 7.3 x 10³/hr at week 6 in males given 150 mg/kg/day compared with 4.3 x 10³/hr in the control group.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased stomach weights seen in 50 and 150 mg/kg/day females at 2 weeks. Testes weights decreased in treated males at week 6.
At 13 weeks mean relative liver and kidney weights were increased in the 150 mg/kg/day males (not statistically significant).

Gross pathological findings:

no effects observed

Description (incidence and severity):

Thickening of the pericardium and an adhesion between the heart and pericardium were noted in a female dosed with 50 mg/kg/day.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological findings were not considered to be related to the toxicity of the test substance.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

One control female killed after 6 weeks had multiple small nodules in the lung (reticulum-cell neoplasm type A).

Other effects:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITYNo behavioural or obvious clinical symptoms were noted in the animals during the course of the study. The two deaths noted in the study were due to accidental intratracheal administration and not attributed to the toxicity of the test substance.BODY WEIGHT AND WEIGHT GAINNo statistically significant differences noted in the study. In the group of animals with the lower testes weight occurred in animals with lower bodyweights.FOOD CONSUMPTIONFood consumption was slightly increased in males receiving 150 mg/kg/day.WATER CONSUMPTIONFood consumption was slightly increased in males receiving 150 mg/kg/day.HAEMATOLOGYNo statistically significant differences.CLINICAL CHEMISTRYNo statistically significant differences.URINALYSISRenal dilution and concentration results did not indicate any significant differences between treated and control animals and no abnormal constituents were noted. Cell excretion was 7.3 x 10³/hour at week 6 in males given 150 mg/kg/day compared with 4.3 x 10³/hour in the control group, this was 70 % higher than controls, however no similar effects were noted in any other group.ORGAN WEIGHTSIncreased stomach weights were seen in 50 and 150 mg/kg/day females at 2 weeks. Testes weights were decreased in treated males at week 6. These were not found to be significant when expressed as relative to bodyweight. At 13 weeks mean relative liver and kidney weights were increased in the 150 mg/kg/day males (not statistically significant). This was considered to be an increase enzyme activity in the liver, metabolising the test substance (coping mechanism) rather than a toxic effect of the test substance. These differences were not accompanied by histopathological changes.GROSS PATHOLOGYOne female in the 50 mg/kg/day at 13 weeks had thickening of the pericardium and an adhesion between the heart and pericardium.HISTOPATHOLOGY: NON-NEOPLASTICIn the female with the thickening of the pericardium, oil droplets were noted in the thoracic cavity, pericarditis and a granulomatous reaction of the pericardium containing oil droplets were noted. One male dosed with 15 mg/kg/day (13 weeks) also demonstrated similar effects. These were considered to be due to misadministration of the dose (intratracheal).Evidence of a mild pulmonary infection, early changes characteristic of glomerulonephrosis and splenic haemosiderin deposition were recorded, however these effects were also noted in the control with comparable severity. Two females in the 150 mg/kg/day groups (13 weeks) also had hydrometra in the uteri.HISTOPATHOLOGY: NEOPLASTICOne control female killed after 6 weeks had multiple small nodules in the lung (reticulum-cell neoplasm type A).

Effect levels

1

Key result

Dose descriptor:

NOEL

Effect level:

15 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

food consumption and compound intake

water consumption and compound intake

other: slight increase in liver and kidney weights

Remarks on result:

other:

Remarks:

No effects on histopathology for both liver and kidney

2

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: food consumption;water consumption and organ weights

Remarks on result:

other:

Remarks:

No effects on histopathology for both liver and kidney. Effects considered adaptive.

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Table 1: Results for bodyweight and food and water consumption

Dose level (mg/kg)

Bodyweight (g) at day

Bodyweight gain (g) at day 95

Mean food consumpation (g/rat/day)

Mean water consumpation (mL/rat/day)

0

32

60

95

Males

0

101

287

376

432

331

16.1

22.3

15

101

288

368

429

328

15.9

22.9

50

104

302

383

446

342

16.4

23.4

150

103

302

381

447

344

17.5**

24.5*

Females

0

88

194

231

258

170

13.4

19.4

15

89

199

241

260

171

13.4

19.8

50

91

203

238

265

174

12.5

18

150

92

201

233

265

173

13.7

20.2

Bodyweights are mean of 15 animals

Food and water values are the means for three cages of five animals

*P<0.05

**P<0.01

 

Table 2: Results of haematological references

Sex and dose level (mg/kg)

No. of rats examined

Hb (g/100 mL)

PCV (%)

RBC (10⁶/mm³)

Retics (% of RBCs)

Leucocytes

Total (10³/mm³)

Differential (%)

N

E

L

M

Male

Week 2

0

5

11.7

41

4.79

2.4

5.0

10

0

89

1

50

5

11.4

41

4.47

3.0

4.6

6

0

92

2

150

5

11.9

40

4.66

2.8

5.5

8

1

89

2

Female

Week 2

0

5

12.1

39

5.04

2.3

7.0

8

1

89

2

50

5

11.6

40

4.54*

1.8

5.6

10

1

88

1

150

5

12.5

41

5.11

1.8

3.5**

11

1

87

1

Male

Week 6

0

5

14.7

45

6.67

1.1

8.3

11

1

87

1

50

5

14.6

45

6.82

1.0

7.4

18

1

80

1

150

5

14.5

44

6.39

1.1

7.6

13

0

86

1

Female

Week 6

0

5

13.6

42

6.17

0.9

6.9

16

1

82

1

50

5

14.9*

44

6.21

1.0

5.5

13

1

85

1

150

5

14.4

43

6.12

1.0

4.7

12

2

85

1

Male

Week 13

0

14

14.3

45

7.18

1.0

6.1

15

1

82

2

15

14

14.4

44

7.08

1.1

5.5

15

1

83

1

50

15

14.2

45

7.32

1.0

6.3

18

1

80

1

150

15

14.3

45

7.24

1.0

7.4

13

1

84

2

Female

Week 13

0

15

14.0

43

6.13

1.1

3.6

13

2

84

1

15

15

13.8

42

5.98

1.1

4.2

13

1

85

1

50

14

13.9

40

6.17

1.3

4.3

10

1

88

1

150

15

14.0

43

9.12

1.1

4.2

14

1

84

1

Hb- Haemoglobin, PCV - packed cell volume, RBC - red blood cells, Retics - reticulocytes, N - neutrophils, E - eosinophils, L - lymphocytes and M - monocytes

 

Table 3: Mean organ weights

Sex and dose level (mg/kg)

No. of rats examined

Relative organ weights (g/100 g bodyweight)

Terminal bodyweight (g)

Brain

Heart

Liver

Spleen

Kidneys

Stomach

Small intestine

Caecum

Adrenals^a

Gonads^b

Pituitary^a

Thyroid^a

Male

Week 2

0

5

0.94

0.47

3.90

0.43

0.93

0.68

4.13

0.46

26

1.11

5.0

-

177

50

5

0.91

0.44

3.83

0.41

0.88

0.69

4.23

0.45

29

1.20

4.9

-

181

150

5

0.96

0.44

3.87

0.43

0.92

0.67

4.35

0.44

27

1.19

5.1

-

176

Female

Week 2

0

5

1.14

0.53

3.88

0.46

0.94

0.78

4.74

0.56

35

98

7.0

-

143

50

5

1.08

0.44

3.92

0.42

0.90

0.85

4.47

0.49

38

106

7.0

-

153

150

5

1.13

0.64

4.11

0.46

0.94

0.85

4.52

0.57

35

108

6.1

-

147

Male

Week 6

0

5

0.65

0.38

3.01

0.30

0.78

0.54

2.69

0.33

18

1.19

3.1

-

317

50

5

0.66

0.39

2.96

0.33

0.79

0.56

2.94

0.34

20

1.17

3.2

-

291*

150

5

0.69

0.38

3.06

0.30

0.82

0.59

2.81

0.35

19

1.20

3.1

-

278*

Female

Week 6

0

5

0.92

0.43

2.92

0.33

0.78

0.69

2.63

0.38

35

135

6.2

-

190

50

5

0.98

0.44

3.09

0.35

0.81

0.70

3.05

0.40

39

141

6.4

-

187

150

5

0.97

0.45

3.18

0.37

0.80

0.66

3.07

0.40

36

158

5.6

-

187

Male

Week 13

0

15

0.47

0.29

2.58

0.19

0.58

0.46

2.32

0.26

15

0.85

2.5

4.0

411

15

14

0.45

0.28

2.53

0.18

0.58

0.46

2.25

0.24

15

0.88

2.3

4.6

405

50

15

0.45

0.30

2.73

0.19

0.62

0.46

2.24

0.25

16

0.87

2.4

4.6

422

150

15

0.45

0.30

2.78*

0.19

0.63**

0.47

2.31

0.25

15

0.85

2.4

4.4

418

Feale

Week 13

0

15

0.71

0.34

2.48

0.25

0.62

0.56

2.84

0.37

27

56

4.6

6.4

252

15

15

0.71

0.35

2.49

0.26

0.62

0.55

2.81

0.30

27

55

4.1

7.3

255

50

14

0.66

0.34

2.50

0.25

0.62

0.55

2.71

0.27

27

61

4.7

6.2

260

150

15

0.69

0.35

2.51

0.25

0.61

0.54

2.66

0.31

27

59

4.7

6.8

258

^aValues expressed in mg/100 g bodyweight

^bValues for ovaries expressed in mg/100 g bodyweight

Values are means for the no. of rats shown

Statistically significant (Student's t test) * P<0.005 **P< 0.01

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test, the test substance 1-phenylethyl acetate induced only minimal effects in male and female rats when dosed up to 150 mg/kg bw/day in corn oil for 13 weeks. In the absence of information to the contrary, the study reports a NOEL of 15 mg/kg bw/day although the authors consider, that the actual NOEL is between 15 and 50 mg/kg bw/day. The NOAEL is considered to be 150 mg/kg bw/day.

Executive summary:

The subchronic toxicity of 1 -phenylethyl acetate was investigated in CFE rats at doses of 0, 15, 50 and 150 mg/kg bw/day (in corn oil). Although not reported as performed in line with a standardised guideline, the methods were comparable to that of OECD 408. Male and female rats were dosed via oral gavage for 13 weeks (with the relevant satellite groups terminated at 2 and 6 weeks), and periodically assessed for signs of toxicity. At the end of the study all remaining animals were sacrificed and assessed for any gross pathological or histopathological changes. Under the conditions of the test, the test substance 1 -phenylethyl acetate induced only minimal effects in male and female rats when dosed up to 150 mg/kg bw/day in corn oil for 13 weeks. In the absence of information to the contrary, the study reports a NOEL of 15 mg/kg bw/day although the authors consider that the actual NOEL is between 15 and 50 mg/kg bw/day. The NOAEL is considered to be 150 mg/kg bw/day.