Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was considered to be 300 mg/kg bw for P generation when CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) orally by gavage for 3 days.

Link to relevant study records
Reference
Endpoint:
reproductive toxicity, other
Remarks:
Uterotrophic Bioassay
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 peer-reviewed journal
Qualifier:
according to
Guideline:
other: OECD Test Guideline 440
Principles of method if other than guideline:
Uterotrophic Bioassay of 2-phenylethyl 2-hydroxybenzoate in mice
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- IUPAC name: 2-phenylethyl 2-hydroxybenzoate
- Common name: Phenethyl salicylate
- Molecular formula: C15H14O3
- Molecular weight : 242.2726 g/mol
- Smiles notation : c1ccc(cc1)CCOC(=O)c2ccccc2O
- InChl: 1S/C15H14O3/c16-14-9-5-4-8-13(14)15(17)18-11-10-12-6-2-1-3-7-12/h1-9,16H,10-11H2
- Substance type: Organic
- Physical state: Solid
Species:
mouse
Strain:
CD-1
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Experimental Animal Tech Co. of Weitonglihua (Beijing, China)
- Age at study initiation: Exact age was not mention immature mice were taken.
- Fasting period before study: No data available
- Use of restrainers for preventing ingestion (if dermal): No data available
- Housing: Animals were house in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): basic diet, ad libitum
- Water (e.g. ad libitum): water ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12 h light: 12 h dark cycle

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
peanut oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 3- fold serial dilution in peanut oil was used to prepare the doses from stock solution.

DIET PREPARATION
- Rate of preparation of diet (frequency): Daily
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): peanut oil
- Concentration in vehicle: 0, 11.1, 33.3, 100 and 300 mg/kg bw
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 days
Frequency of treatment:
daily
Remarks:
0, 11.1, 33.3, 100 and 300 mg/kg bw
No. of animals per sex per dose:
Total: 60
0 mg/kg bw : 12
11.1 mg/kg bw: 12
33.3 mg/kg bw : 12
100 mg/kg bw : 12
300 mg/kg bw : 12
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
17β-estradiol was used as the positive control( 10, 50 and 400 µg/kg bw/day)
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data available
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. Mortality observed

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
not specified
Postmortem examinations (parental animals):
uteri weight were weighted.
Postmortem examinations (offspring):
not specified
Statistics:
Data are presented as the mean ± SD.
Reproductive indices:
not specified
Offspring viability indices:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Mortality: No effect on survival of treated female mice was observed as compared to control.

Body weight: No effect on body weight was observed in all the treated dose group as compared to control.

Organ weight: significant increase in uterine weight were observed at 33.3 mg/kg bw as compared to control. But when compared with 100 and 300 mg/kg bw not indicated statistical significance.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
mortality
body weight and weight gain
organ weights and organ / body weight ratios
other: No effect observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Number of mice used, number of mice that died during the experiment, arrival body weights and final body weights in the mouse uterotrophic assay. Data are presented as the mean ± SD.

Chemicals

Doses (mg/kg/day)

N (No. of deaths) 

Arrival weighta(g)

) Final weight (g)

E2

10µg/kg/day

12

7.71 ± 0.67

12.05 ± 1.37

 

50 µg/kg/day

12

7.49 ± 0.63

12.10 ± 0.96

 

400 µg/kg/day

11 (1)

7.65 ± 0.65

12.37 ± 1.14

Control

0

12

7.57 ± 0.65

12.02 ± 0.53

PES

11.1

12

7.66 ± 0.56

12.02 ± 0.42

 

33.3

12

7.69 ± 0.74

11.92 ± 0.80

 

100

12

7.67 ± 0.91

12.07 ± 0.72

 

300

12

7.67 ± 0.87

11.71 ± 0.57

aThe body weight on the day (PND 19) of arrival.

Conclusions:
NOAEL was considered to be 300 mg/kg bw for P generation when CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) orally by gavage for 3 days.
Executive summary:

In a Uterotrophic Bioassay, CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) in the concentration of 0, 11.1, 33.3, 100, 300 mg/kg/day in Peanut oil from PND 21 to PND 24. No effect on survival and body weight of treated female mice were observed as compared to control. Significant increase in uterine weight were observed at 33.3 mg/kg bw as compared to control. But when compared with 100 and 300 mg/kg bw not indicated statistical significance. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation when CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) orally by gavage for 3 days.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Data is Klimisch 2 and from peer-reviewed journal
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity: Oral

In a study, 2-phenylethyl 2-hydroxybenzoate has been investigated for oral reproductive toxicity to a greater or lesser extent. Study based on in vivo experiments in rodents, i.e. most commonly in mice for 2-phenylethyl 2-hydroxybenzoate and summarized below.

In a experimental study conducted by Zhangaet al(Toxicology Letters 209 (2012) 146– 153), CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) in the concentration of 0, 11.1, 33.3, 100, 300 mg/kg/day in Peanut oil from PND 21 to PND 24. No effect on survival and body weight of treated female mice were observed as compared to control. Significant increase in uterine weight were observed at 33.3 mg/kg bw as compared to control. But when compared with 100 and 300 mg/kg bw not indicated statistical significance. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation when CD-1 female mice were treated with Phenethyl salicylate (IUPAC name: 2-phenylethyl 2-hydroxybenzoate) orally by gavage for 3 days.

Thus, based on the above study on 2-phenylethyl 2-hydroxybenzoate, it can be concluded that NOAEL value is 300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-phenylethyl 2-hydroxybenzoate can be Not classified for reproductive toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the above study on 2-phenylethyl 2-hydroxybenzoate, it can be concluded that NOAEL value is 300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-phenylethyl 2-hydroxybenzoate can be Not classified for reproductive toxicity.