1-phenylethanol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from NTP report.

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Toxicology and carcinogenesis studies of a-methylbenzyl alcohol in rats

Author:

NTP TECHNICAL REPORT

Year:

1990

Bibliographic source:

NATIONAL TOXICOLOGY PROGRAM, 1990

Reference 2

Reference Type:

secondary source

Title:

EFFECT OF PHEHYLETHYL ALCOHOL (PEA) ON PREGNANCY OF THE RAT

Author:

NTRL report

Year:

1986

Bibliographic source:

NTRL report,OTS0509772-1,1986

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: refer below principle

Principles of method if other than guideline:

The study was performed to evaluate carcinogenic, reproductive and developmental effect of phenylethyl alcohol in rats.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-phenylethanol

EC Number:

202-707-1

EC Name:

1-phenylethanol

Cas Number:

98-85-1

Molecular formula:

C8H10O

IUPAC Name:

1-phenylethan-1-ol

Test material form:

liquid

Details on test material:

- Name of test material: 1-phenylethan-1-ol
- IUPAC name: 1-phenylethanol
- Molecular Formula: C8H10O
- Molecular weight: 122.166g/mol
- Smiles: c1(ccccc1)C(C)O
- InChI: 1S/C8H10O/c1-7(9)8-5-3-2-4-6-8/h2-7,9H,1H3
- Substance type: Organic
- Physical state: Liquid (Clear colourless)

Specific details on test material used for the study:

No data

Test animals

Species:

rat

Strain:

other: CrL.3 COBS CD (SD) BR strain

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Limited.
- Age at study initiation: No data available
- Weight at study initiation: 170 - 242 g (group average range)
- Fasting period before study: No data available
- Housing: Animals were housed individually in a controlled environment in suspended galvanised metal cages equipped with solid sides and back, wire mesh front, floor and top.
- Diet (e.g. ad libitum): S.F. Laboratory Diet No 1, ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimatization period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 2°C
- Humidity (%):53 ± 11%
- Air changes (per hr): 13 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

dermal

Type of inhalation exposure (if applicable):

not specified

Vehicle:

unchanged (no vehicle)

Remarks on MMAD:

No data

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- 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): Water
- Concentration in vehicle: 0, 140, 430 or 1400 mg/kg
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
-According to A.M. Api et.al. (RIFM fragrance ingredient safety assessment, α-methylbenzyl alcohol, CAS registry number 98-85-1) systemic absorption was assumed to be 100% by oral, dermal and inhalation route.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The purity of samples from each of the four different sources was checked by direct injection onto a flame ionization gas chromatography. A Fluka standard of 99.5% was used as a reference.
.

Details on mating procedure:

- M/F ratio per cage: Time-mated rats were delivered from the vendor.
- Length of cohabitation: Not Available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: The day of mating, as judged by the appearance of sperm in the vaginal smear or by the presence of a vaginal plug was considered as Day 0 of pregnancy.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility.:No data
- Further matings after two unsuccessful attempts: [no / yes (explain)]:No data
- After successful mating each pregnant female was caged (how):No data
- Any other deviations from standard protocol:No data

Duration of treatment / exposure:

15 days, i.e. from Day 6 of gestation until sacrifice on Day 20 or gestation.

Frequency of treatment:

Daily, on Day 6 and up to and including Day 15 of pregnancy.

Duration of test:

15 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.14, 0.43 or 1.40 ml/kg/day = 0, 140, 430 or 1400 mg/kg bw
Basis:nominal conc.

No. of animals per sex per dose:

120 females
0 mg/kg: 25 females
140 mg/kg: 35 females
430 mg/kg: 25 females
1400 mg/kg: 35 females

Control animals:

yes, concurrent vehicle

Details on study design:

Further details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): The 120 animals were assigned to four groups by computerised stratified randomisation to give approximately equal initial mean bodyweights
- Other: No data available

Examinations

Maternal examinations:

Clinical signs
All animals were regularly handled and observed daily for obvious changes or signs of reaction to treatment. Any local skin irritation resulting from treatment was scored on each day of the dosing period on a numerical basis.

Mortality:
Any animals that died or were killed for humane reasons were weighed and subjected to post mortem examination.

Food consumption:
Food consumption was measured from weighday to weighday.

Body weights:
All rats were weighed initially (=Day 1 of gestation) and on Days 3 and 6, thereafter, on alternate days through to Day 20 of pregnancy.

Hematology:
On the morning of sacrifice, samples of blood were withdrawn, under light ether anaesthesia, from the orbital sinus of 15 control and 13 high dose rats (as two high dose rats in this batch had already died).
Parameters examined:
Packed cell volume (PCV), Haemoglobin (Hb), Red call count (RDC), Mean corpuscular haemoglobin concentration (MCHC), Mean corpuscular volume, Total white cell count (WBC Total), Platelet count (PLTS), Differential WBC counts and Cell morphology.

Clinical chemistry:
On the morning of sacrifice, samples of blood were withdrawn, under light ether anaesthesia, from the orbital sinus of 15 control and 13 high dose rats (as two high dose rats in this batch had already died).
Parameters examined:
Total Protein, Albumin (Alb), Globulin (Glob), Urea nitrogen (Urea N),Creatinine (Creat), sodium (Na), Potassium (K), Calcium (Ca), Inorganic phosphorus (P), Chloride (Cl), Cholesterol (Chol), Glucose, Alkaline phosphatese (AP), Glutamic-pyruvic transaminase (GPT) and Glutamic-oxaloacatic transaminase (GOT).

Gross pathology:
On Day 20 of pregnancy the animals were killed, dissected and examined for congenital abnormalities and macroscopic pathological changes in maternal organs. The liver and kidneys of 15 control and 13 high dose rats were weighed.

Histopathology:
The liver and kidneys of 15 control and 13 high dose rats were investigated by histological examination.

Ovaries and uterine content:

The ovaries and uteri were examined immediately to determine the number of corpora lutea, the number and distribution of live young, the number and distribution of embryonic/fetal deaths and individual fetal weight from which the litter weight was calculated.

Fetal examinations:

The fetuses were weighed and was examined externally, and was examined for fetal abnormalities and malfunctions as well as for skeletal examinations.

Statistics:

Statistical analysis of incidences of abnormalities was considered unnecessary given the results obtained.

Statistical analyses were, however, performed routinely on litter data, using the litter as the basic sample unit and non-parametric tests (Jonckheere and Kruskal-Wallis) as these values rarely follow a 'normal' distritution. Analysis of covariance followed by William’s test was used for assessing intergroup differencas in mean organ weights. The Kruskal-Wallis test was also used to analyse intergroup differences in the results of the Biochemical and Haematological examinations.

Indices:

Not Available

Historical control data:

Not Available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Signs of reaction to treatment were seen for the highest dosage group (1400 mg/kg/day). Signs started to develop on about Day 12 of pregnancy, six days after start of treatment and escalated during the remainder of the dosing period. Other less frequently observed signs included suspected blood on the undercage tray paper, slight edema in the dosing area and perineal staining.

Towards the end of the dosing period a brownish colored deposit became apparent in the dosing area of all the highest dosage group animals.

With the exception of a single non-pregnant animal treated with 430mg/kg/day which had a hunched posture and was walking on its toss on Day 16 of the study, there were no overt signs of reaction to treatment at the intermediate or low dosage.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

At 1400 mg/kq/day, two animals were found dead on Day 13 of pregnancy (seven days after start of treatment) and one had already been killed on Day 12 due to moribund condition. All three showed signs of reaction typical for this group. In addition, the latter animal had shown rapid respiration, blood in the urine and was apparently unable to walk. At autopsy, however, the only macroscopic observation appeared to be slight congestion of the dorsal subcutis of one of the animals.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Subsequent mean weight gain of rats treated with 430 or 1400 mg/kg/day did not show any substantial difference from control throughout the remainder of the study. In contrast, mean weight gain of animals treated at 1400 mg/kg/day was markedly retarded. Although substantial recovery of body weight occurred after dosing ceased, parity with the control group was not regained and mean bodyweight at termination was noticeably depressed.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intake of rats treated with 1400 mg/kg/day became noticeably suppressed towards the end of the treatment period, but approached control levels after cessation of treatment.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

A higher value for white cell count were observed in animals treated with 1400 mg/kg/day.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

As compared to control, lower levels in urea nitrogen, creatinine, GPT, GOT and alkaline phosphatase were observed when animals were treated with 1400 mg/kg/day.

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):

There were no statistically significant differences between control and test groups in respect of liver and kidney weights adjusted for differences in body weight.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Despite the marked clinical response observed at 1400 mg/kg/day, there were no findings amongst surviving animals in any group at termination which were considered to be related to treatment.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:Yes
Details on maternal toxic effects:

Clinical signs: Signs of reaction to treatment were seen for the highest dosage group (1400 mg/kg/day). Signs started to develop on about Day 12 of pregnancy, six days after start of treatment and escalated during the remainder of the dosing period. Other less frequently observed signs included suspected blood on the undercage tray paper, slight edema in the dosing area and perineal staining.Towards the end of the dosing period a brownish colored deposit became apparent in the dosing area of all the highest dosage group animals. With the exception of a single non-pregnant animal treated with 430mg/kg/day which had a hunched posture and was walking on its toss on Day 16 of the study, there were no overt signs of reaction to treatment at the intermediate or low dosage.

Mortality: At 1400 mg/kq/day, two animals were found dead on Day 13 of pregnancy (seven days after start of treatment) and one had already been killed on Day 12 due to poor condition. All three showed signs of reaction typical for this group. In addition, the latter animal had shown rapid respiration, blood in the urine and was apparently unable to walk. At autopsy, however, the only macroscopic observation appeared to be slight congestion of the dorsal subcutis of one of the animals.

Food consumption: Food intake of rats treated with 1400 mg/kg/day became noticeably suppressed towards the end of the treatment period, but approached control levels after cessation of treatment.

Body weights: Subsequent mean weight gain of rats treated with 430 or 1400 mg/kg/day did not show any substantial difference from control throughout the remainder of the study. In contrast, mean weight gain of animals treated at 1400 mg/kg/day was markedly retarded. Although substantial recovery of body weight occurred after dosing ceased, parity with the control group was not regained and mean bodyweight at termination was noticeably depressed.

Hematology: A higher value for white cell count were observed in animals treated with 1400 mg/kg/day.

Clinical chemistry: As compared to control, lower levels in urea nitrogen, creatinine, GPT, GOT and alkaline phosphatase were observed when animals were treated with 1400 mg/kg/day.

Organ weights: There were no statistically significant differences between control and test groups in respect of liver and kidney weights adjusted for differences in body weight.

Gross pathology: Despite the marked clinical response observed at 1400 mg/kg/day, there were no findings amongst surviving animals in any group at termination which were considered to be related to treatment.

Histopathology: No data available

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

1 400 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: toxic effects observed

2

Dose descriptor:

NOAEL

Effect level:

430 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

food consumption and compound intake

other: Maternal toxicity

Remarks on result:

other: No developmental toxic effects observed

Maternal abnormalities

Abnormalities:

not specified

Localisation:

not specified

Results (fetuses)

Fetal body weight changes:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Mean values for litter weight and mean fetal weight were essentially comparable with those of controls in dose group 140 or 430 mg/kg/day but There was a consequent significant reduction in litter weight. Reduction in the litter weight was further enhanced by significantly lower mean weight of surviving fetuses in dose group 1400mg/kg /day

Reduction in number of live offspring:

effects observed, treatment-related

Description (incidence and severity):

After treatment with 140 or 430 mg/kg/day:There were no instances of total litter loss at either dosage and the overall incidence of embryo-fetal deaths was similar to, or below, that of the control group.
There was a consequent significant reduction in litter size at dose 1400mg/kg/day.

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

effects observed, treatment-related

Description (incidence and severity):

Morphological change was observed in 160 of the 161 fetuses. A variety of skeletal and soft tissue changes were observed and the degree of change varied between individuals, including anophthalmia/microphthalmia, ventricular septal defects, and defects of the thoracic ribs and occurrence of cervical rib(s).

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: No effects

Details on embryotoxic / teratogenic effects:

Examination of maternal uterus:

Mean ovulation rate (as assessed by corpora lutea count) and mean pre-implantation loss of the treatment groups compared favorably with control, resulting in higher mean implantation rates. The overall pregnancy rate was similar for all groups.

After treatment with 1400 mg/kg/day: The incidence of embryo-fetal deaths was significantly increased and extended to total litter loss in 5/23 litters. Death predominantly occurred early in pregnancy.

There was a consequent significant reduction in litter size and in litter weight. Reduction in the litter weight was further enhanced by significantly lower mean weight of surviving fetuses.

Morphological change was observed in 160 of the 161 fetuses. A variety of skeletal and soft tissue changes were observed and the degree of change varied between individuals, including anophthalmia/microphthalmia, ventricular septal defects, and defects of the thoracic ribs and occurrence of cervical rib(s).

After treatment with 140 or 430 mg/kg/day: There were no instances of total litter loss at either dosage and the overall incidence of embryo-fetal deaths was similar to, or below, that of the control group.

Mean values for litter size, litter weight and mean fetal weight were essentially comparable with those of controls.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

external malformations

other: Developmental toxicity : Morphological changes in fetus

Remarks on result:

other: No developmental toxic effects observed

2

Dose descriptor:

LOAEL

Effect level:

430 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

external malformations

other: Developmental toxicity :morphological changes in fetuses

Remarks on result:

other: morphological chenges observed

Fetal abnormalities

Abnormalities:

not specified

Localisation:

other: not specified

Overall developmental toxicity

Developmental effects observed:

yes

Lowest effective dose / conc.:

1 400 mg/kg bw/day (nominal)

Treatment related:

yes

Relation to maternal toxicity:

not specified

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

NOEAL and LOEAL for maternal toxicity in female rats were considered to be 430 and 1400 mg/kg/day, respectively. NOAEL and LOEL for developmental toicity was considered to be 140 and 430 mg/kg/day after exposure to phenylethyl alcohol.

Executive summary:

In a developmental and reprotoxicity study, the toxic effect of phenylethyl alcohol were evaluated in time-mated female CrL:COBS CD (SD) BR rats. The test chemical was administered dermally at a dosage of 0, 140, 430 or 1400 mg/kg per day during days 6-15 of pregnancy. In an emergence of an evidence,according to Api et.al. (RIFM fragrance ingredient safety assessment, alpha-methylbenzyl alcohol, CAS registry number 98 -85 -1), systemic absorption of the test chemical was assumed to be 100% by oral, dermal and inhalation route.

The study was terminated and the animals killed at day 20 of gestation.Signs of reaction to treatment were seen for the highest dosage group (1400 mg/kg/day). With the exception of a single non-pregnant animal treated with 430 mg/kg/day which had a hunched posture and was walking on its toss on Day 16 of the study, there were no overt signs of reaction to treatment at the intermediate or low dosage. Body weight and food intake of rats treated with 1400 mg/kg/day became noticeably suppressed towards the end of the treatment period, but approached control levels after cessation of treatment. Subsequent mean weight gain of rats treated with 430 or 140 mg/kg/day did not show any substantial difference from control. The results from the hematology showed a higher value for white cell count in animals treated with 1400 mg/kg/day. Despite the marked clinical response observed at 1400/kg/day, there were no findings in gross pathology amongst surviving animals in any group at termination which were considered to be related to treatment. When investigating the litters from females treated with 1400mg/kg/day, the incidence of embryo-fetal deaths was significantly increased and extended to total litter loss in 5/23 litters. Death predominantly occurred early in pregnancy. There was also a consequent significant reduction in litter size and in litter weight. Reduction in the litter weight was further enhanced by significantly lower mean weight of surviving fetuses. In addition, morphological change was observed in 160 of the 161 fetuses, and a variety of skeletal and soft tissue changes were seen, where the degree of change varied between individuals. No such changes of results were observed in litters from females treated with 140 or 430 mg/kg/day. Therefore, NOEAL and LOEAL for maternal toxicity in female rats were considered to be 430 and 1400 mg/kg/day, respectively. NOAEL and LOEL for developmental toicity was considered to be 140 and 430 mg/kg/day after exposure to phenylethyl alcohol.