Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acutely hazardous after ingestion but not following skin contact.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Near guideline, GLP animal experimental study, available as published report, fully adequate for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS-Source: Blue Spruce Farm, Altamont, New York- Sex: Male and female- Weight at study initiation: 180-280 g- after fasting- Acclimation period: Five days - Housing: Rats housed individually in stainless steel -wire mesh cages. - Diet Wayne Lab Blox, ad libitum, checked daily and added or replaced as needed- Water availability- fresh tap water, fit for human consumption ad libitum: ENVIRONMENTAL CONDITIONS- Temperature (°C): 22 ± 3 °C Humidity (%): 30-70- Photoperiod (hrs dark / hrs light): 12/12.
Route of administration:
oral: gavage
Vehicle:
other: other: 0.25% methylcellulose
Details on oral exposure:
Volume administration: 5 ml/kg
Frequency and duration of administration: Once
Rational for route of administration: Potential route for human exposure
Doses:
0, 1000, 1600, 2000, 2500 and 3200 mg/kg
Rational for dose selection: Based upon the results of the dose-range finding study
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Five groups of 10 rats, 5 female and 5 male, were fasted for 18 hr. The test material was administrated once orally, by gavage at 1000, 1600, 2000, 2500 and 3200 mg/kg. Dose levels were based on a preliminary dose-range finding study.
Duration of observation period following administration: 14 days- Frequency of observations: animals were observed at one, four, twenty-four hours after dosing and twice daily for fourteen days. - Necropsy of survivors performed: yes- Other examinations performed: clinical signs, body weight.
Statistics:
The LD50 and 95% CI limits were calculated according to the method of Litchfield and Wilcoxon.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 603.3 mg/kg bw
Based on:
test mat.
95% CL:
1 399.6 - 1 850.4
Sex:
male
Dose descriptor:
LD50
Effect level:
1 692.6 mg/kg bw
Based on:
test mat.
95% CL:
1 433.3 - 1 998.9
Remarks on result:
other: The data generated did not lend itself to the method of Litchfield and Wilcoxon
Mortality:
None of the animals died at 1000 mg/kg dose level. Five of 10 died at 1600 mg/kg dose level. Nine of 10 died at 2000 mg/kg dose level.
Clinical signs:
other: Signs observed included diarrhea, decreased activity, poor grooming, piloerection, exophtalmus, ataxia, chromodacryorrhea, hypersensitivity, hyperactivity, decreased body tone, tremors, dyspena, wheezing, prostration, abnormal stance, ptosis, abnormal gai
Gross pathology:
Necrospy: Necropsy of animasl revelead distended stomachs with hemorrhages of the glandular mucosa, red foci on the thymus, discolored adrenals and fluid- filled fladders. Terminal necrospy revelead no visible lesions in the remaining animals.
Interpretation of results:
sligthly toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 was determined to be 1609.3 mg/kg (male and female, combined).
Executive summary:

The acute oral toxicity of Phenyl ethyl alcohol was studied in a GLP-compliant, not following a specific guideline. The animals were exposed once to 0, 1000, 2000, 2500 and 3600 mg/kg bw/day by oral gavage and observed for 14 days. There were no toxicologically significant effects at doses <1000 mg/kg. The rats were observed immediately and at 1, 4, 24 hours after dosing and twice daily for 14 days in order to evaluate clinical signs and mortality.The calculated LD50 for male and female animals was determinated to be 1609.3 mg/kg with 95% confidence limits of 1399.6 to 1850.4 mg/kg according to the method Litchfield and Milcoxon. Necroscopy of the animals dying on the study revealed distended stomachs with hemorrhages present on the mucosa. Distended bladders, red foci on the thymus and discoloured adrenals were also observed. Terminal nescropy revealed no visible lesions in any the surviving animals.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 603 mg/kg bw
Quality of whole database:
Adequate for assessment

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non guideline, GLP animal experimental study, available as published report, but not fully adequate for assessment
Principles of method if other than guideline:
The protocol has been designed with reference to the Environmental Protection Agency, Pesticide Program, and the proposed TOSCA Health Effect Test Standard.
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Ltd.
- Age at study initiation: 8 weeks old
- Weight at study initiation: 175 to 225 g/ 200-250 at onset of acclimatation
- Fasting period before study:
- Housing: individually housed in stainless steel, wire meshd- bottom cages.
- Diet (e.g. ad libitum): Certified Purina Laboratory Rat Chow diet
- Water (e.g. ad libitum): tap woter ad libitum except during the four hour inhalation exposure
- Acclimation period: 1week minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
inhalation: aerosol
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
- Exposure chamber volume: 27'' cube (400 liter volume) stainless steel whole body exposure
- Method of holding animals in test chamber:
- Source and rate of air: 45 L/min
- Method of conditioning air: Air was decontamined by using HEPA filter, an activated charcoal filter and liquid scrubber prior to eliminating it from the facility
- System of generating particulates/aerosols: An aerosol of the test article was generated using a Thermo System Inc. six jet atomizer- used at pressure of 9 psig with 2 jets in operation.
- Method of particle size determination:
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber: Monitored hour by hours by means of remote sensors (YSI model 705 Temperature Probe and 91 HD Dew Point Hygrometer)- Temperature and humidity were respectively 25.4 °C and 34.8%:

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly air samples were collected for measurements of chamber concentration at rate of 5 L/min for two minutes, through a preweighted Gelman glass fibre filter paper. Chamber concentration was calculated from the increase in weight of the filter and volume of air sample.
Hourly air samples from inhalation chamber for particle size analysis were withdrawn and passed through a Casella cascade Impactor.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable):
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal concentration was 4.63 mg/l resulting in a measured chamber concentration of 1.38 mg/l.
No. of animals per sex per dose:
1 Group: 5 females and 5 males
Control animals:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.63 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: All animals survived to scheduled study termination
Mortality:
No deaths.
Clinical signs:
other: Non clinical signs of possible toxicological importance were observed.
Body weight:
Small body weight losses were observed on the days following the exposure. The losses were recovered by Day 7.
Gross pathology:
LUNGS: Multiple greyish- green focal areas scattered throughout alla lobes with several dark red areas present on the right cranial lobe. Congestion, mild, diffuse.
KIDNEYS: Slightly pale
Other findings:
LUNGS: Chronic repsiratory disease, modeate to severe. Pulmonary edema and congestion, only one section.
BRONCHIAL LYMPH NODES: Enlarges
KIDNEYS: No pathological alterations
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Conclusions:
Phenyl Ethyl Alcohol administrated by inhalation route did not produce any systemic toxicity in the albino rat. Lung and bronchial outcomes were considered to be spontaneous and caused by a mild infection with murine respiratory mycoplasmosis. Pulmonary edema was attributed to euthanasia. The acute LC50 was concluded to be greater than 4.63 mg/l expressed in terms of nominal concentration.
Executive summary:

The study investigated the effect of Pheny ethyl alcohol in females and males of Sprague- Dawley rats. 25 males and 25 females were exposed by inhalation route to 4.63 mg/l (nominal concentration), which resulted in a measured chamber concentration of 1.38 mg/l of the test material for 4 hours.

The treatment was carried on in a 27'' cube stainless steel and glass whole body exposure chamber and signs of mortality and visible toxic effect were hourly recorded. The observation period covered 14 days after dosing. Body weight, gross pathology, histopatology, clinical signs were recorded. The results of the study demonstrated that there were no moralities due to the exposure to Phenyl Ethyl Alcohol. Change at polmonar, bronchial and kidney level, partial loss of weight were observed, but they were attributed to infection.The acute LC50 was concluded to be 4.63 mg/l expressed in terms of nominal concentration and it is not classifiable for acute inhalation toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Limited information indicates LC50 exceeds 1.38 mg/l

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, Pennsylvania
- Age at study initiation:
- Weight at study initiation: 2-3 kilograms
- Fasting period before study:
- Housing: individual cages sized in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Resources, national research Council
- Diet (e.g. ad libitum): Wayne Rabbit Ration, ad libitum
- Food analysis: there were no contaminants
- Water (e.g. ad libitum): Fresh tap water, fit for human consumption was available ad libitum, using 16 ounce glass bottles with rubber stopper and stainless steel sipper tube or an automatic watering system supplied by Edstrom Indistries Inc. Waterford, Wisconsin.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C+/- 3°C
- Humidity (%): 30-70%:
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hrs night

IN-LIFE DATES: From: To:
Type of coverage:
occlusive
Vehicle:
other: administred as received
Duration of exposure:
24 hrs
Doses:
2000 mg/kg (Limit Test)
1600, 2500, 4000 mg/kg
No. of animals per sex per dose:
Total: 10
Male: 5
Female: 5
Details on study design:
Pre-test
The trunk of the animals was shaved in order to have at least 10% (about 240 cm) of the dorsal body surface area available for application of the test material. Immidiately prior dosing, the skin of five males and five females for the 2000 mg/kg limit test and the skin of 2 males and 2 females pr group for the definitive LD50 determination was abraded by making four epidermal incisions with a clean needle to produce bleeding. The test material was applied directly onto the exposed skin of the animals. A layer of gauze was wrapped around the animals to cover the dosed area. The animal was wrapped with rubber dam and an Ace bandage to retard evaporation. The test article was held in contact with the skin of the animals for 24-hrs. After that, the test site was washed to remove any remaining material.

Observations:
Observation were recorded at 2 and 4 hrs after the 24 hrs period of exposure and twice daily thereafter for 14 days. Body weights were recorded weekly and at the study termination. All rabbits were sacrificed by CO2 inhalation od Day 14 and a gross necropsy was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 535 mg/kg bw
Based on:
test mat.
95% CL:
1 769 - 3 634
Remarks on result:
other: One of 8 animals died at 1600 mg/kg level, 5 of 8 died at 2500 mg/kg and 6 of 8 died at 4000 mg/kg.
Mortality:
Six of the 10 animals died at 2000 mg/kg. One of the eight animals died at the 1600 mg/kg level, five of eight died at 2500 mg/kg and six of eight died at 4000 mg/kg.
Clinical signs:
other: Signs observed at 2000 mg/kg/day are: diarrhea, semi-prostation, body drop, prostation, abnormal gait, decreased activity and abnormal stance. Signs observed at the 1600, 2500 and 4000 mg/kg levels included: erythema, body drop, decreased activity, decrea
Other findings:
Necropsy of those animals dying on study revelead discolored adrenals and hemorrhages present in the muscle underlying the application site. Necropsy of animals exposed to 1600 mg/kg level, 2500 mg/kg and 4000 mg/kg revealed hemorrhages on muscle underlying the application site and dark fluid present in the bladder. Dried exudate around the oral and nasal cavities was also observed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based upon the observation made in the acute dermal toxicity test in rabbits, the estimated acute dermal LD50 for phenylethyl alcohol was considered to be 2535 mg/kg with 95% confidence limits of 1769 to 3634 mg/kg.
Executive summary:

The acute dermal toxicity potential of phenylethyl alcohol was investigated using 3 groups of 8 rabbits (4 males and 4 females). The test item was administrated at dose levels of 1600, 2500 and 4000 mg/kg. At all dosage levels the main signs observed were prostration, decreased activity, which disappeared after 4 -5 days from the treatment. Mortaility occurred for 1 of the 8 animals exposed to 1600 mg/kg, and for 6 of 10 animals exposed to 2000 mg/kg for 5 of 8 animals treated with 2500 mg/kg and for 6 of 8 rabbits treated with 4000 mg/kg. In conclusion, the estimated acute dermal LD50 of phenylethyl alcohol was considered to be 2535 mg/kg with 95% confidence limits of 1769 to 3634 mg/kg, under the condition of the study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 535 mg/kg bw
Quality of whole database:
Adequate for assessment

Additional information

Information is available from studies that have investigated the acute toxicity of Phenyl ethyl alcohol after oral, dermal and inhalation exposure.

The first acute oral toxicity was carried on by Pharmakon Research International, Inc (1982) in a near guideline study conducted under GLP-conditions. The animals were given a single dose of Phenylethyl alcohol at levels of 0, 1000, 2000, 2500 and 3600 mg/kg bw/day by oral gavage and then observed for 14 days. The calculated LD50 for male and female animals was determined to be 1609.3 mg/kg with 95% confidence limits of 1399.6 to 1850.4 mg/kg according to the method Litchfield and Wilcoxon. The acute oral toxicity of Phenylethyl alcohol in the rat was also investigated by Carpenter et al. (1973) in an early non-guideline non-GLP toxicity study. Doses were arranged in a logarithmic series and differed by a factor of two. Animals were then observed for 14 d post-treatment. Based on the limited information contained in this publication, the acute oral LD50 for Phenyl ethyl alcohol was 2.46 ml/kg bw (equivalent to 2510 mg/kg bw, based on a density of 1.0202). Of these two studies, the one conducted by Pharmakon Research International, Inc (1982) is considered of higher reliability since the study methods and results are clearly described and reported; only limited information is available from the study of Carpenter et al. (1973).

The acute inhalation toxicity of Phenyl ethyl alcohol was investigated by Bio Research Laboratories Ltd (1980), using male and female Sprague-Dawley rats. The animals (n=25 per sex) were exposed whole body to a nominal concentration of 4.63 mg/l, equivalent to a measured concentration 1.38 mg/l, for 4 hrs. There was no mortality, either during exposure or in a subsequent 14- day observation period. The acute LC50 was greater than 1.38 mg/l.

The acute dermal toxicity of Phenyl ethyl alcohol was investigated by Pharmakon Research International, Inc (1983) in a near-guideline, GLP compliant study. The test item was administered as a single treatment to 3 groups of 8 rabbits (4 males and 4 females) at dose levels of 1600, 2500 and 4000 mg/kg. At all dosage levels the main clinical signs observed were prostration and decreased activity, which disappeared after 4 -5 days following treatment. Mortality occurred in 1 of the 8 animals exposed to 1600 mg/kg;,in 6 of 10 animals exposed to 2000 mg/kg; in 5 of 8 animals treated with 2500 mg/kg; and in 6 of 8 rabbits treated with 4000 mg/kg. In conclusion, the estimated acute dermal LD50 of Phenyl ethyl alcohol was 2535 mg/kg with 95% confidence limits of 1769 to 3634 mg/kg, under the condition of the study. The acute dermal toxicity of Phenyl ethyl alcohol was also investigated by Carpenter et al. (1973) in an early non-guideline, non-GLP study. The test was carried out using 4 male New Zealand White rabbits. The test sample was applied to clipped skin under an impervious plastic film for a 24 hr exposure period, and the animals then observed for 14 d post-treatment. Based on the results obtained from the study, the acute dermal LD50 for Phenyl ethyl alcohol was 0.79 ml/kg bw (equivalent to 806 mg/kg bw, based on PEA density= 1.0202 g/cm3). Of these two studies, the one conducted by Pharmakon Research International, Inc (1983) is considered of higher reliability since the study methods and results are clearly described and reported; only limited information is available from the study of Carpenter et al. (1973).

Justification for classification or non-classification

In accordance with Regulation (EC) No. 1272/2008, classification Acute Toxicity category 4 (H302: Harmful if swallowed) is required for acute oral toxicity. No classification is necessary for acute effects following dermal or inhalation exposure.