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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-08-17 to 1984-11-23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
no
Remarks:
At the time of the study conduct, GLP was not compulsory. However, the study was conducted in accordance with the principles of GLP.
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: 20% of the pure active substance in water
Details on test material:
- Name of test material: DOPA-Glycinate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 4–7 weeks
- Weight at study initiation: Males: 110–150 g, Females: 100–140 g
- Fasting period before study: yes, overnight
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 40-70
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: dest. water
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
Group 1: 500.0 mg/mL
Group 2: 195.3 mg/mL
Group 3: 312.5 mg/mL
Group 4: 800.0 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
Doses:
Group 1: 5000 mg/kg bw
Group 2: 1953 mg/kg bw
Group 3: 3125 mg/kg bw
Group 4: 8000 mg/kg bw
(as "product by process", 20%)
No. of animals per sex per dose:
Sighting study: 4 animals per group (2 females and 2 males)
Main study: 10 animals per group (5 females and 5 males)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs: Observations were made within 15 and 30 minutes, 1, 2 and 4 hours after dosing and subsequently in surviving animals at least once daily throughout an observation period of 14 days.
Body weights: The body weight of each animal was recorded on the day before treatment, on the day of treatment and again seven and fourteen days after treatment.
- Necropsy of survivors performed: yes
Statistics:
Calculation of LD50 for male and female rats based on probit method of Finney (1984).

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
660 mg/kg bw
Based on:
act. ingr.
Sex:
female
Dose descriptor:
LD50
Effect level:
863.6 mg/kg bw
Based on:
act. ingr.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
756.6 mg/kg bw
Based on:
act. ingr.
Sex:
male
Dose descriptor:
LD50
Effect level:
3 300 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
4 318 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 783 mg/kg bw
Based on:
test mat.
Mortality:
Mortalities occurred between two hours after dosing and day 6. There were deaths among rats dosed at 3125 mg/kg bw and at all higher dose levels. All rats receiving 8000 mg/kg bw test item died.
Clinical signs:
On the day of treatment piloerection were observed in all of the 10 test animals of all dose groups. Animals of the middle dosed groups showed increased signs of hunched posture (9/10 animals of dose level 3125 mg/kg bw; 4/10 animals of dose level 5000 mg/kg bw) and lethargy (8/10 animals of dose level 3125 mg/kg bw; 4/10 animals of dose level 5000 mg/kg bw). Changes in breathing frequency were observed in a few animals (1 to 4) of all dosed groups. All surviving animals of the middle dosed groups appeared normal on day eight after treatment.
Body weight:
All surviving rats showed bodyweight gain at the end of the observation period.
Gross pathology:
All animals of the lowest dose group showed no remarkable necropsy findings.
In the higher dosed groups the following findings were noted: congestion in liver and spleen (6 animals of dose group 8000 mg/kg bw, 3 animals of dose group 5000 mg/kg bw, and 1 animals of dose group 3125 mg/kg bw), intensive reddening of the mucosal surface of the stomach (7 animals of dose group 8000 mg/kg bw, 3 animals of dose group 5000 mg/kg bw, and 2 animals of dose group 3125 mg/kg bw), autolysis (6 animals of dose group 8000 mg/kg bw, 3 animals of dose group 5000 mg/kg bw, and 4 animals of dose group 3125 mg/kg bw). High graded hyperaemia and partially with yellow liquid filled gastrointestinal tract were noted in 2 animals of each dose level group. Overloading of stomach was observed in the dose level group 5000 mg/kg bw (1/10 animals) and in the dose level group 8000 mg/kg bw (5/10 animals).

Any other information on results incl. tables

Table A6.1.1-1:Acute toxicity in rats.

Group

Dose [mg/kg bw]*

Number of dead/ number of investigated

Time of death

Observations

Males

Females

Total

1

5000

3/5

3/5

6/10

Day 1–5

Piloerection, hunched posture, lethargy, eye lids half-closed, eye lids nearly closed, eye lids closed, heavy breathing, loamy coloured anal and genital tract, salivation, aggression

2

1953

0/5

0/5

0/10

Piloerection, hunched posture, lethargy, eye lids half-closed, increased breathing, emaciation

3

3125

4/5

1/5

5/10

Day 2–6

Hunched posture, lethargy, piloerection, eye lids half-closed, eye lids nearly closed, eye lids closed, increased breathing, heavy breathing, lacrimation, brown coloured anal and genital tract

4

8000

5/5

5/5

10/10

Day 1–3

Piloerection, lethargy, hunched posture, prone position, eye lids closed, eye lids half-closed, increased breathing

LD50 value [mg/kg bw]

 

3300

4318

3783

 

 

*) based on test substance as manufactured (20% aqueous solution)

Applicant's summary and conclusion

Interpretation of results:
other: Category 4
Remarks:
Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
The oral LD50 (rat, male) of DOPA-Glycinate was determined to be 660 mg a.i/kg bw.
Executive summary:

The acute oral toxicity of DOPA-Glycinate (20% aqueous solution) was tested in Sprague Dawley rats. 4 Groups of 10 animals, 5 male and 5 female rats, received single oral doses of 1953, 3125, 5000 or 8000 mg/kg bw of the test item by gavage. Animals were then observed for 14 days. Although not a guideline study, the method used was consistent to method B.1 (92/69/EEC) in all important aspects.

Death was noted between two hours after dosing and day 6. There were deaths among rats dosed with 3125 mg/kg bw and at all higher dose levels. All rats receiving 8000 mg/kg bw died. On the day of treatment piloerection were observed in all of the 10 test animals of all dose groups. Further frequently occurred symptoms were hunched posture and lethargy in animals of the middle dosed groups. All surviving animals of the middle dosed groups (3125 and 5000 mg/kg bw) appeared normally on day eight after treatment.

The LD50 in terms of test material (20% aqueous solution) was calculated at 3300 mg/kg bw for males, 4318 mg/kg bw for females and 3783 mg/kg bw for combined sexes.

These values correspond to 660 mg a.i./kg bw for males, 863.6 mg a.i./kg bw for females and 756.6 mg a.i./kg bw for combined sexes.

According to the criteria laid down in Regulation (EC) No 1272/2008, DOPA-Glycinate is classified for Acute toxicity, Category 4.