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Description of key information

Four studies were performed to determine the acute oral toxicity of alpha-Lipoic acid.

The studies from the year 1974, using mice and rats as test animals, show silmilarities to the OECD-guideline 401 adopted later in 1987.

Because of more than 3 dosing levels and a greater number of animals, these studies give a more precise result.

In rats the LD50 is 1200 mg/kg BW (m + f).

In mice the LD50 is 502 mg/kg BW (m) and 460 mg/kg BW (f).

The studies from the year 2013 follow an other guiudeline (OECD 423) and are not compareble to the older studies.

The

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11/1973 - 12/1973
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
OECD 401: at least 5 rodents of each sex in each group; at least three dose levels; limit test at least 2000 mg/kg b.w. This Study: 10 rats of each sex in each group; 6 dose levels, spaced with factor 1.26
GLP compliance:
not specified
Test type:
standard acute method
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Surviving animals were held in macrolon cages (B II) at 24.0 +/- 0.5 °c and 60 +/- 3 % relative humidity.
During 4 weeks after treatment behaviour, feed and water intake and body weigth were observed.
After 4 weeks animals were dissectet and examinded macroscopic.
Route of administration:
oral: gavage
Vehicle:
other: 1 % aequous methyl-hydroxyethylcellulose gel MH300
Doses:
Lowest dose: 504 mg/kg b.w.
Step per dose: factor 1.26
Highest dose: 1590 mg/kg b.w.
No. of animals per sex per dose:
10
Control animals:
no
Statistics:
Litchfield and Wilcoxon
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 1 190 mg/kg bw
Based on:
test mat.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 1 210 mg/kg bw
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Median lethal dose (LD50)
- Male rats: 1190 (1090 - 1300) mg/kg b.w.
- Female rats: 1210 (1110 - 1320) mg/kg b.w.
Executive summary:

Symptoms of intoxication showed:

- Sedation

- ataxis (635 mg/kg b.w.)

- reduced feed intake (1000 mg/kg b.w.)

- abdominal position

- slow and breathing

- tonic-clonic spasms (1260 mg/kg b.w.)

Death occured within 2 and 24 h after after treatment after tonic-clonic spasms.

Lowest lethal dose: 1000 mg/kg b.w.

Surviving animals recovered within 2 d.

Necopsy showed pale and parencymatic organs in animals that died after treatment. Other animals showed no pahological findings.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
10/1973 - 12/1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
OECD 401: at least 5 rodents of each sex in each group; at least three dose levels; limit test at least 2000 mg/kg b.w. This Study: 10 mice of each sex in each group; 9 dose levels, spaced with factor 1.26
GLP compliance:
not specified
Test type:
standard acute method
Test material information:
Composition 1
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
Surviving animals were held in macrolon cages (B II) at 24.0 +/- 0.5 °c and 60 +/- 3 % relative humidity.
During 4 weeks after treatment behaviour, feed and water intake and body weigth were observed.
After 4 weeks animals were dissectet and examinded macroscopic.
Route of administration:
oral: gavage
Vehicle:
other: 1 % aequous methyl-hydroxyethylcellulose gel MH300
Doses:
Lowest dose: 129 mg/kg b.w.
Step per group: factor 1.26
Highest dose: 790 mg/kg b.w.
No. of animals per sex per dose:
10
Control animals:
no
Statistics:
Litchfield u Wilcoxon
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 502 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 460 mg/kg bw
Based on:
test mat.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Median lethal dose (LD50)
- Male mice: 502 (452 - 556) mg/kg b.w.
- Female mice: 460 (418 - 506) mg/kg b.w.
Executive summary:

Symptoms of intoxication showed:

- Sedation (159 mg/kg b.w.)

- ataxis

- abdominal position

- reduced feed intake (200 mg/kg b.w.)

- slow and deep breathing (318 mg/kg b.w.)

- nervousness and tremor

- tonic-clonic spasms (400 mg/kg b.w.)

Death occured within 0.5 and 3 h after treatment after tonic-clonic spasms.

Lowest lethal dose: 400 mg/kg b.w.

Surviving animals recovered within 3 d.

Necopsy showed no pahological findings.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2013-05-07 - 2013-06-19
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
The test with concentrated impurities is not comparable with the older tests in wich the acute oral toxicity of alpha-Lipoic acid was determined by an other method.
For that reason two tests under the same conditions were performed:
- alpha-Lipoic acid as described in the composition (1.2)
- alpha-Lipoic acid with concentrated impurities (50.1 % impurites)
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Test animals: healthy feamale, non-pregnant, nulliparous rats
Temperature: 22 +/- 3 °C
Relative humidity: 55 +/- 10 %
Arificial light: 12 h light, 12 h dark
Diet: free access
Water: free access
Cages: IVC III H
Acclimatization : at least 5 days under laboratory conditions
Route of administration:
oral: gavage
Vehicle:
DMSO
Remarks:
Diluted in cottinseed oil 1:6.67
Doses:
2000 mg/kg b.w.
300 mg/kg b.w.
No. of animals per sex per dose:
2000 mg/kg b.w.: 3 female rats
300 mg/kg b.w.: 6 female rats (2 groups à 3 animals)
Control animals:
no
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
ca. 500 mg/kg bw
Based on:
test mat.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The median lethal dose of alpha-Lipoic acid after single oral administration to female rats, observed over a period of 14 d is:
LD50 cut-off(rat): 500 mg/kg b.w.
Executive summary:

2000 mg/kg b.w., step 1: 2 animals died on day of treatment

1 animals was found dead on day after administration

300 mg/kg b.w., step 2: all animals survived

300 mg/kg b.w., step 3: all animals survived

Surviving animals showed symptoms of toxicity, but symptoms recovered after 3 days post dose.

Necropsy:

Step 1 (2000 mg/kg b.w.)

3 animals showed yellowish residues of the test item in the stomach

Step 2 (300 mg/kg b.w.)

3 animals showed no specific findings

Step 3 (300 mg/kg b.w.)

3 animals showed no specific findings

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
20113-05-15 - 2015-06-26
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
unsuitable test system
Justification for type of information:
This Study was performed to show the toxicity of the impurities in alpha-Lipoic acid.
For that reason the impurities were concentrated up to 50.1 %.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001-12-17
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002-12
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Test animals: healthy feamale, non-pregnant, nulliparous rats
Temperature: 22 +/- 3 °C
Relative humidity: 55 +/- 10 %
Arificial light: 12 h light, 12 h dark
Diet: free access
Water: free access
Cages: IVC III H
Acclimatization : at least 5 days under laboratory conditions
Route of administration:
oral: gavage
Vehicle:
DMSO
Remarks:
Diluted in cottinseed oil 1:6.67
Doses:
2000 mg/kg b.w.
300 mg/kg b.w.
No. of animals per sex per dose:
2000 mg/kg b.w.: 3 female rats
300 mg/kg b.w.: 6 female rats (2 groups à 3 animals)
Control animals:
no
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
ca. 500 mg/kg bw
Based on:
test mat.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The median lethal dose of alpha-Lipoic acid with concentrated impurities after single oral administration to female rats, observed over a period of 14 d is:
LD50 cut-off(rat): 500 mg/kg b.w.
Executive summary:

This Study was performed to show the toxicity of the impurities in alpha-Lipoic acid.

2000 mg/kg b.w., step 1: 1 animal died spontaneously on day of treatment

2 animals were found dead on study day 2

300 mg/kg b.w., step 2: 1 animal was found dead on study day 2

300 mg/kg b.w., step 3: 1 animal was sacrificed for ethical reasons on day of treatment

All remaining animals survived until the end of the study.

Necropsy:

Step 1 (2000 mg/kg b.w.)

2 animals showed a bloated stomach with residues of the test item

1 animal showed yellowish residues of the test item in the stomach

Step 2 (300 mg/kg b.w.)

1 animal showed residues of the test item in the stomach

1 animal showed a bloated colon

1 animal showed no specific findings

Step 3 (300 mg/kg b.w.)

2 animals showed no specific findings

1 animal showed a bloated stomach

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 200 mg/kg bw

Additional information

Justification for classification or non-classification

According to the CLP regulation test substances with an LD50 between 300 and 2000 mg/kg b.w. are classified as hamful (category 4).