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Description of key information

LD50 of L-Phenylalanine was determined to be 16g/kg bw in an acute oral toxicity study with rats. L-Phenylalanine is practically non-toxic.

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:
Dec. 1970 to 1971-09-20
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reference:
Composition 0
Qualifier:
no guideline followed
Guideline:
other: An OECD or other international guideline for acute oral toxicity was not available at the the year of the study. The study is similiar to OECD 403
Deviations:
not applicable
Principles of method if other than guideline:
Groups of ten rats (five males and five females) were administered 0, 10 and 16g/kg bw L-phenylalanine and observed during two weeks for mortality.
GLP compliance:
no
Remarks:
study performed prior to implementation of GLP
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
other: CFY strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Carworth Europe, Alconbury, Huntingdon
- Weight at study initiation: 62 - 123 g
- Fasting period before study: 20 hours before dosing (and 4 hours after dosing)
- Housing: caged in groups according to sex and age

Route of administration:
other: Solution in water or as suspension in 1 % methyl cellulose and administered by gastric intubation.
Vehicle:
other: water or methyl cellulose plus water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30% solution in water or 30% suspension in 1% methyl cellulose

MAXIMUM DOSE VOLUME APPLIED:
Maximum dosage volume of 53.3 ml/kg bodyweight, equivalent to a maximum practical dose of 16g amino acid /kg bodyweight.
Dosage volumes in excess of 20 ml/kg were given in divided doses at two hourly intervals.
Doses:
0, 10 and 16 g/kg bw.
Rats dosed with the vehicle alone served as controls.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: once a week
- Necropsy of survivors performed: yes
- Other examinations performed: body weight/behaviour
Statistics:
Method of Litchfield J.T., Wilcoxon F (1949), J. Pharmac. exp. Ther. 96, 99
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 10 000 - <= 16 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 16 000 mg/kg bw
Based on:
test mat.
Dose descriptor:
approximate LD50
Effect level:
ca. 16 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: median Iethal oral dose
Mortality:
Three female rats died; one dosed at 10g/kg and two dosed at 16g/kg bw. Death occurred wlthin 46 hours of dosing and was preceded by coma. Autopsy of animals that died did not reveal any specific cause of death.
Clinical signs:
Lethargie behaviour was observed shortly after dosing.
Recovery of survivors, as judged by external appearance and behaviour was apparently complete within 3 days.
Body weight:
Bodyweight increases of treated rats were slightly depressed for the first week (except for males dosed at 10g/kg) but were normal during the second week.

Group mean body weight with 0g test substance (control groups):
Male: day 0: 83 g, day 7: 141 g, day 14: 201 g
Female: day 0: 86 g; day 7: 144 g; day 14: 183 g

Group mean body weight with 10g test substance:
Male: day 0: 87 g, day 7: 148 g, day 14: 213 g
Female: day 0: 81 g; day 7: 131 g; day 14: 171 g

Group mean body weight with 16g test substance:
Male: day 0: 79 g, day 7: 129 g, day 14: 175 g
Female: day 0: 82 g; day 7: 132 g; day 14: 168 g
Gross pathology:
Autopsy findings were normal.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
An acute oral toxicity study was performed with groups of 5 male and 5 female rats. The results indicate that the median lethal oral dose (LD 50) of L-phenylalanine is ca. 16g/kg bw.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
16 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

According to Annex VII REACH, for substances manufactured or imported in quantities of 1 to 10 tonnes, the standard information requirements for acute toxicity comprise studies on acute toxicity by oral route only.

Key study:

An acute oral toxicity study was performed with groups of 5 male and 5 female rats. The results indicate that the median lethal oral dose (LD 50) of L-phenylalanine is ca. 16g/kg bw. This study was performed prior to the implementation of GLP and availibility of an OECD guideline or any other international test guideline; thus its reliability is Klimisch 2. Nevertheless, the study is considered to be comparable to an OECD 403 guideline study and is chosen as key study for acute oral toxicity.

Supporting Studies:

An acute oral toxicity study was performed with groups of male rats, mice and rabbits with doses up to 5000 mg/kg aspartame. No deaths occurred within 7 days of dosing in any of the species tested or at any of the doses used, and no abnormalities in behaviour were noted. This indicates an LD50 of aspartame of > 5000 mg/kg bw. Read-across from aspartame to L-Phenylalanine was applied. The LD50 of L-Phenylalanine was calculated to be >2806 mg/kg bw, using the ratio of molecular weights of the test substance and L-Phenylalanine.

Read-across from aspartame to L-Phenylalanine was applied because of their structural similarity and the metabolism of aspartame.

Aspartame is a methylester of the aspartic acid/phenylalanine dipeptide. Following oral exposure, aspartame undergoes hydrolysis catalysed by esterases and dipeptidases leading to release of its individual components (aspartate, phenylalanine and methanol). This may occur either in the lumen of the gastrointestinal tract or within intestinal mucosal cells; either way, it is the individual components which undergo absorption [lit.: EFSA. Supporting Publications 2013:EN- 399. [191 pp.]. Available online: www.efsa.europa.eu/publications].

Another supporting study indicates, both phenylalanine and aspartame in doses up to 10 g failed to alter food intake or hunger, mood and arousal in normal weight adult males. The highest phenylalanine load administered in this study was greater than two times the usual daily human intake [lit.: National Research Council. Improvement of Protein Nutriture. Washington, DC: National Academy of Sciences, 1974.]

Justification for selection of acute toxicity – oral endpoint

key study

Justification for classification or non-classification

Based on the data available no classification for acute toxicity (oral toxicity, dermal toxicity, inhalation toxicity) is required.


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