L-Tyrosine, N-(aminocarbonyl)-3-methoxy-O,.alpha.-dimethyl-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1990-1991

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP. The study is one week shorter than recommended. The concentration of the test material in the food is not precisely determined. Only one sex was examined insted of both. Evaluation of clinical signs, pathology is less then guideline recommendation.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Principles of method if other than guideline:

The study is one week shorter than recommended. The concentration of the test material in the food is not precisely determined.
Only one sex was examined insted of both. Evaluation of clinical signs, pathology is less then guideline recommendation.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tyrosine, N-(aminocarbonyl)-3-methoxy-O,α-dimethyl-

EC Number:

608-271-2

Cas Number:

28861-00-9

Molecular formula:

C13H18N2O5

IUPAC Name:

Tyrosine, N-(aminocarbonyl)-3-methoxy-O,α-dimethyl-

Details on test material:

Name of test material (as cited in study report): Ureido-karbonsav
- Substance type: organic
- Physical state: white crystalline powder
- Stability under test conditions: stable
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation: 197.75 +/- 9.33 g
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): LATI food
- Water (e.g. ad libitum): ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: mixed with food

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): max. 5 days storage.
- Mixing appropriate amounts with (Type of food): 125 or 250 mg/kg doses mixed in 8 g/100 g food.
- Storage temperature of food: room temperature, in dark glass.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

12 weeks

Frequency of treatment:

daily feeding

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
250 mg/kg
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
125
Basis:
nominal in diet

No. of animals per sex per dose:

10-12 male rats,

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: acute per os LD50: 5000 mg/kg, 1/20; 1/40XLD50
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: 0-12 week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: 1/20 LD50; 1/40 LD50

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 week, 12 week
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters checked Glu, Htk, Fvs, Se, St, Jn, Eo, Mo, MNS were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: No data
- How many animals:
- Parameters checked: Glu, Htk, Fvs, Se, St, Jn, Eo, Mo, MNS were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: 1/20 LD50; 1/40 LD50
- Battery of functions tested: sensory activity / grip strength / motor activity / other: peripheral nerve conductivity

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes

Statistics:

Probit analysis to determine subacute per os LD50.
t-probe method.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality, no signs.

BODY WEIGHT AND WEIGHT GAIN
Slightly decreased body weight gain compared to control group.
Coltrol group body weight gain was 271 %.
1/40XLD50 dose body weight gain 250 %.
1/20XLD50 dose body weight gain 256 %.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Not measured.

FOOD EFFICIENCY
Not measured.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study).
Not measured.

OPHTHALMOSCOPIC EXAMINATION
Not examined.

HAEMATOLOGY
Heamatokrit, qualitative and quantitative white count, SE, St, Jn, Eo, Mo, MNS was determined.
Effects was not observed compared to control group and the normal values.

CLINICAL CHEMISTRY
Blood glucose was tested in both control and 1/20XLD50, 1/40XLD50 doses at 6th week, and 12th week.
Significant difference was not observed compared to control group.

URINALYSIS
Not determined.

NEUROBEHAVIOUR
Learning process was examined by labyrinth methodology. No harmful effects was observed to the learning process of rats.
Peripheral nerve activity was observed by electromyography. Effects was not observed compared to control group, and the measured values at beginning of the study.

ORGAN WEIGHTS
Relative organ weight (brain, thymus, lung, heart, spleen, kidney, testes) was determined.
Significant decrease was observed in liver (13%), and spleen (16%) relative organ weight at dose 1/20xLD50.


HISTOPATHOLOGY:
Abnormality in thymus and lung tissue was observed. In thymus: increase in lymphoproliferative centers.
In lung: interstitialis-, broncho-, lipoid pneumonia and splitting of alveoli.

Effect levels

1

Dose descriptor:

dose level: LD50/20

Effect level:

other: not determined

Based on:

test mat.

Sex:

male

Basis for effect level:

other: See effects at Section Details on results.

2

Dose descriptor:

dose level: LD50/40

Effect level:

other: not determined

Based on:

test mat.

Sex:

male

Basis for effect level:

other: See effects at Section Details on results.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Subacute 12th week feeding study was performed on male rats.
Performance and evaluation of the study has limited relaibility.
Results has not shown significant harmful effect of the substance.