[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

13-week repeated dose toxicity study of L-tyrosine in rats by daily oral administration

Author:

Shibui Y., Manabe Y., Kodama T., Gonsho A.

Year:

2016

Bibliographic source:

Food Chem Toxicol. 87:55-64

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tyrosine

EC Number:

200-460-4

EC Name:

Tyrosine

Cas Number:

60-18-4

Molecular formula:

C9H11NO3

IUPAC Name:

tyrosine

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system 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.)

Administration / exposure

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 / concentrations

Doses / concentrations 1

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

600 spores/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes

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

Examinations

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).

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

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-dependend

Mortality:

no mortality observed

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

Endocrine findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

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.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

- 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.

Effect levels

Key result

Dose descriptor:

other: LD50

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

Applicant's summary and conclusion

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:

O-phospho-L-tyrosine dissociates in aqueous solutions. As according to REACH regulation only publicly available data has to be provided with the Registration dossier for on-site isolated intermediates in a tonnage band of < 1,000 t/a. Thus, information on the paren compound L-tyrosin is considered relevant and will be used for the registration dossier of O-phospho-L-tyrosine.

 

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.