5-(dithiolan-3-yl)valeric acid

Endpoint summary

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

Reference

Reference 1

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

Qualifier:

equivalent or similar to guideline

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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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.

Reference 2

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

Qualifier:

equivalent or similar to guideline

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

Species:

mouse

Strain:

NMRI

Sex:

male/female

Details on test animals or test system 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.

Reference 3

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 which 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) this study
- alpha-Lipoic acid with concentrated impurities (50.1 % impurities) Study titled "disregarded"

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system 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:

cotton seed oil

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

Reference 4

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 %.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

2001-12-17

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002-12

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system 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:

cotton seed oil

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

Value:

1 200 mg/kg bw

Quality of whole database:

Result is based on a OECD study rated Klimisch 1. Therefore the quality is considered good.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

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).