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Key value for chemical safety assessment

Acute toxicity: via oral route

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Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reference:
Composition 0
Principles of method if other than guideline:
No OECD guideline was followed, however after acute dosing the animals were observed for 2 weeks and multiple parameters were assessed.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Remarks:
pathogen-free
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Weight at study initiation: 250-300g
- Fasting period before study: overnight
- Housing: 2 per stainless steel cage (7 X 7 X 10 in.)
- Diet: ad libitum Purina Rat Chow (5012)
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12-hr light (0600-1800 hr)/12-hr dark cycle
Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) methylcellulose, 0.1% (v/v) polysorbate 80 and distilled water
Details on oral exposure:
DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
309 or 618 mg/kg
No. of animals per sex per dose:
15
Control animals:
yes
Remarks:
15 vehicle control animals per dose and d-amphetamine as positive control reported elsewhere (Mullenix et al., 1989. Generation of dose-response data using activity measures. / Am. Coll. Toxicol. 8, 185-197)
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency behavioral testing: daily
- Blood samples: immediately after behavioral testing
- Euthanisation: overdose pentobarbital
- Behavioral tests: A computer pattern recognition system was used. A control and test rat are placed simultaneously on either side of a clear Plexiglas box separated by a clear partition with small holes. The animals could see and smell each other while they explored the novel environment. Two video cameras at one frame per second were used to monitor and record the rats' spontaneous behavior. The video signals are transferred to a MICRO VAX I and a VAX 11/750 for pattern analysis and behavioral classification of the data. The specific behaviors identified by the computer consist of 5 major body positions: stand, sit, rear, walk, lying down; and eight modifiers: blank (no recognized ac- tivity), groom, head turn, turn, look, smell, sniff, wash face.
Statistics:
A student's t-test was applied, and a p < 0.05 was required for statistical significance.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 618 mg/kg bw
Based on:
test mat.
Mortality:
No animals died.
Clinical signs:
No significant altered bahavioral effect were observed at any dose. Tyrosine did not affect spontaneous behavior.
Body weight:
Not determined.
Gross pathology:
Not evaluated.
Other findings:
- Plasma level: elevated plasma concentrations of tyrosine after dosing
- Positive control: Amphetamine clearly increased the total time the rats engaged in walking, turning, and head turning, and thus influenced the overal behavior.
Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not acute toxic and the LD50 is > 618 mg/kg bw.
Executive summary:

In the current study the effect of a single oral administration of a high dose of tyrosine was investigated. More in detail the behavior of the rats was evaluated with a computer pattern recognition system. The study was not according to OECD or GLP, however, the animals were observed for 2 weeks. There were 2 dosing groups, 309 and 618 mg/kg, each containing 15 animals and each group was linked to a control group of 15 animals. Amphetamine was used as positive control.

No animals died and no adverse effects were observed during the course of the study. Amphetamine clearly increased the total time the rats engaged in walking, turning, and head turning, and thus influenced the overal behavior.

No LD50 was determined in the study, however, we can derive it and state that the LD50 is > 618 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: OECD 408
GLP compliance:
not specified
Test type:
other: 90-days oral repeated dose toxicity study
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 6 weeks old
- Weight at study initiation: males 176 - 200 g, females 151 - 173 g
- Housing: individually in suspended, stainless-steel cages
- Diet (e.g. ad libitum): free acces to certified rodent diet sterilized by gamma irradiation (CRF-1; Oriental Yeast Co., Ltd., Tokyo, Japan).
- Water (e.g. ad libitum): free access to tap water
- Acclimation period: 5 - 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 h a day (from 7 a.m. to 7 p.m.)
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
L-tyrosine suspensions of 20, 60 and 200 mg/mL were prepared once a day and mixed just prior to each administration.
Dose volume: 10 mL/kg
Doses:
200, 600 and 2000 mg/kg bw/d
No. of animals per sex per dose:
10
Control animals:
yes
Remarks:
vehicle controls
Details on study design:
- Duration of observation period following administration: 90 days
- Frequency of observations and weighing: day 1 and 2 and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, heamatology, clinical chemistry, ophthalmology, food and water consumption
Statistics:
Body weight, food consumption, water consumption, urinalysis (expect qualitative analysis), hematology, blood chemistry, and organ weight data were recorded using a MiTOX RDT system. Numerical data obtained during the study were used to calculate group mean values and standard deviations. Group variances for the appropriate parameters were compared using Bartlett's method (significant at p < 0.01 in two-tailed test). When the differences between group variances were not significant, Dunnett's multiple comparison method was applied to determine the significance of differences between the control group and each L-tyrosine-treated group (significant at p < 0.05 in two-tailed test) (Dunnett, 1955). If the Bartlett's test indicated significant differences between group variances for a given parameter, that parameter was compared among groups using the Steel's multiple comparison method for mean ranking (significant at p < 0.05 in two-tailed test).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died.
Clinical signs:
Crust formation was seen in the neck in a few animals in all groups including the control group, and was not considered to be treatment-related because a similar finding was also seen in the control group and its incidence did not increase in a dose-dependent manner.
Loss of fur in the forelimb that was bilaterally seen in one or two rats in the L-tyrosine treated groups, was considered to be incidental because this finding is historically quite common.
Body weight:
No differences between controls and treated groups.
Gross pathology:
Significant increases, or a tendency thereof, were found in absolute and relative weights of liver and kidneys in males and females at 2000 mg/kg bw/day. Decreased absolute adrenal weight (right side) was noted in females at 600 and 2000 mg/kg bw/day, but was considered to be incidental because it was seen unilaterally, was not associated with a changes in relative adrenal weight, and individual weight was within the range of variation in the control group.
Other findings:
- Stomach: Edema of the cornified layer at the limiting ridge (minimal to slight) was seen in 2 females at 600 mg/kg bw/day and in 3 males and 4 females at 2000 mg/kg bw/day. Edema of the cornified layer at the forestomach (minimal) was seen in 1 female at 2000 mg/kg bw/day.
- Liver: Centrilobular hypertrophy of hepatocytes (minimal) was seen in 2 males and 2 females at 2000 mg/kg bw/day.
- Kidney: Diffusely increased hyaline droplets were seen in the proximal tubules (minimal to moderate) in 9 males at 2000 mg/kg bw/day with higher grade and incidence than in the control.
Conclusions:
We can assume that the LD50 for males and females will be > 2000 mg/kg bw/d because after 90 days of dosing no animal died.
Executive summary:

In this current study the potential toxicity of L-tyrosine was evaluated in a 13-week repeated-dose oral toxicity study in rats according to OECD 408. The study was not GLP. L- tyrosine was administered by gavage to 4 groups each consisting of 10 males and 10 females. The doses were 0 (vehicle: water), 200, 600 or 2000 mg/kg bw/day.

No deaths occured during the administration period in any of the study groups. No L-tyrosine-related changes were observed in clinical signs, body weight, food and water consumption, ophthalmology or necropsy.

Some L-tyrosine-related changes were observed in the stomach, the liver and kidneys.

Additionally, significant changes were seen in biochemical parameters.

Cataract formation was not observed in this study at any dose level.

Even though this study is not an acute toxicity study, based on the above results, we can assume that the LD50 for males and females will be > 2000 mg/kg bw/d because after 90 days of dosing no animal died.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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

Acute oral toxicity

In the study of Mullenix the administration dose was not as high as recommended in the guideline. Also, the focus of the study was behavioral observation. However, no animal died during the observation period of 2 weeks. Additionally, there is a 90-days repeated dose toxicity study available according to OECD 408 in which rats were orally dosed up to 2000 mg/kg bw for 13 weeks and the no animal died during this period. Taking together in a weight-of-evidence approach no new acute toxicity test is needed, as the available information is sufficient.

Justification for classification or non-classification

As no mortality was observed in the available publications at a dose of 2000 mg/kg bw/d, the test item is not to be classified for acute oral toxicity.