Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 214-071-2 | CAS number: 1077-28-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
- Wistar rat: 61.9 mg/kg BW
- Beagle Dog: 14.7 mg/kg BW
- Wistar rat: 21.5 mg/kg BW
- Beagle Dog: > 50.0 mg/kg BW
Sub-acute (28 d), sub-chronic (26 w) and chronic (2 a) repeated dose toxicity was assessed in rats.
Sub-acute (28 d) and sub-chronic (26 w) repeated dose toxicity was assessd in Beagle dogs.
In the sub-acute Studies the following NOAEL were assessted:
The HED wich can be calculated from these NOAEL by deviding by the specific conversion factor are comparable.
It can be concluded that rat and dog show a similar sensitivity against alpha-Lipoic acid after daily administration for 28 d.
In the sub-chronic studies the following NOAEL were assessted:
In the chronic study with Sprague-Dawley rats the LOAEL is 60 - 180 mg/kg BW.
The NOAEL was not reported. Most findings in the low dose (20 mg/kg BW) and the intermediate dose (60 mg/kg BW) group can be regarded as age-related.
It can be concluded that the NOAEL is beween 20 and 60 mg/kg BW.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993-09-13 - 1995-05-08
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 1991-07-19
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age: m 7 month, f 6-7 month
B.w. m 10.5 - 17.1 kg, f 7.7 - 14.5 kg
Caging: Boxes 6.0 m x 1.2 m
No of animals per box: 3
Diet: Standard dog diet ad libitum
Water: ad libitum in drinking water quality
Room temperature: 23.5 - 26 °C
Relative humidity: 30 - 55 %
Lighting: 6 a.m. - 6 p.m. artificial lighting, 6 p.m. - 6 a.m.natual dark rhythm - Route of administration:
- oral: capsule
- Details on route of administration:
- gelatine capsules (12 x 30 mm)
- Vehicle:
- unchanged (no vehicle)
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- once daily (a.m.)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 14.7 mg/kg bw/day (nominal)
- Remarks:
- low dose
- Dose / conc.:
- 31.6 mg/kg bw/day (nominal)
- Remarks:
- intermediate dose
- Dose / conc.:
- 68.1 mg/kg bw/day (nominal)
- Remarks:
- high dose
From day 3 of administration onwards: 56.2 mg/kg b.w. (m)
From day 16 of administration onwards: 56.2 mg/kg b.w. (f)
From day 17 of administration onwards: 46,4 g/kg b.w. (m + f) - No. of animals per sex per dose:
- 3 m + 3 f
- Control animals:
- yes
- Observations and examinations performed and frequency:
- Mortality: twice daily (a.m. and p.m.)
Behaviour and general condition: daily
Food consumption: daily, staring with 2nd pretest week
B.w.: Once a week, staring with 2nd pretest week
Reflexes: Pain, pupil, corneal and patella reflexes, once a week staring with 2nd pretest week
Heart rate, body temperature: once a week staring with 2nd pretest week, before administration each
Ophthalmology: before first administration and in week 4, all animals
ECG: before first subtance administrationand in week 4 before administration
Clinical chemistry and hematology: before first substance administration and in weeks 1 and 4
Urine: week 5 by punctation of the bladder during autopsy - Sacrifice and pathology:
- Anesthesia: Rompun(R) and T61(R), exsanguination
Gross Necropsy: all animals -> external surface of body, orifices, cranial, toracic and abdominal cavities and their contents.
All gross lesions, adrenal glands (r/l), aorta, axillary lymph node, bone (femur and sternum), bone marrrow smear (from sternum), brain (cerebrum, cerebellum, medulla/pons), caecum, cervix, colon, duodenum, epididymides (r/l), gallbladder, heart, ileum, injection sites, jejunum, kidneys (r/l), liver, lungs, main stem bronchi, mammary gland, mesenteric lymph node, oesophagus, ovaries (r/l), pancreas, parathyrois glands (r/l), peripheral nerve, pituitary gland, prostate, rectum, salivary glands (parotid, submaxillary, sublingual), skeletal muscle, skin, spinal cord (cervical, thoracic, lumbar segments), spleen, stomach, testes (r/l), thymus, thyroid gland (both lobes), tongue, trachea, urinary bladder, uterus, vagina.
Organ weigths: Adrenals (r/l), brain, heart, kidneys (r/l), liver, lungs, ovaries (r/l), pituitary, prostate, spleen, testes (r/l), thyroids (r/l).
Expression as absolute values and relative to b.w. recoreded in week 4.
Fixation: All organes and tissues exept eyes and bone marrow smears -> 10 % formalin
Eyes -> SUSA fixative 4 - 16 h, thereafter 10 % formalin
Bone marrow smears -> air dried
Staining: All organs and tissues -> embedded in parafine wax, sectioned at 4 µm and stained with H&E
Additional sections of kidneys -> periodic acid Schiff reaction
Cryostate sections of liver and one kidney -> Oil red 0 - Statistics:
- Mean and SD: each group and sex
B.w. and organ weigts: DUNNET-Test
Clinical Parameters, ECG, hematology, clinical chemistry: DUNNETT-Test (normal distribution), otherwise STEEL-Test
Significances:
DUNNETT: * p < 0.05, ** p < 0,01
STEEL: + p < 0.05 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Behaviour and general condition were dose dependently influenced in mid and high dose animals in extend, incidence, and severity during the treatment period.
Low dose animals were free of toxic symptoms.
Intermediate dose males had serve hypokinesia, decrease of muscle tone (abdominal position), salivation, vomitus and sunken sides. Females of this group showed salivation and vomitus only.
High dose animals of both sexes had in addition th mid dose males symptoms like coordination disturbances, loss if righting reflex (lateral position), and diarrhea. The animals were in a poor general condition. One out of three females had serve clonic convulsions temprorarily. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One male animal of group 3 and two male animals of group 4 had to be killed in extremis.
One female animal of group 4 had to be killed in extremis. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased b.w. in high dose animals.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dose dependent reduced.
After dose reduction in the high dose group food intake normalized to control group level. - Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes in some white blood cell parameters in individual high dose animals.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Substance related changes in individual high dose animals.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Immunological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes in white blood cell parameters may show an immunologicel effect.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- High dose male: increased wight of liver and thyroid gland, decreased weight of prostate
Hight dose females: increased weights of lung and liver. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Pale discolored liver.
Ulcerations in pyloric mucosa of stomach.
Pale discolored kidneys. - Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 14.7 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 31.6 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Key result
- Dose descriptor:
- other: lethal dose range
- Effect level:
- >= 56.1 - <= 68.1 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- mortality
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 31.6 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 31.6 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Conclusions:
- On the basis of the present 4-week oral toxicity study with alpha-Lipoic acid it can be concluded that most of the observed clinical, clinical pathological and pathological findings are substance related.
- Executive summary:
The low dose of 14.7 mg/kg b.w. was free of toxic symptoms, clinical pathological and histopathological changes.
Further findings in mid and high dose groups give an indication that liver and kidney are clearly involved als target organs for the test subatance.
The results of the macro- and microscopic examinations inclusive organ weight determination did distinctly confirm the results of the clinical chemistry investigations and they are in good correspondence to these findings.
Under the present experimental conditions it can be stated, that alpha-Lipoic acid exerts distinct toxic effects in doses of 31.6 and 68.1/56.2/46.4 mg/kg b.w. A dose range between 68.1 and 56.2 mg/kg b.w. represents the beginning lethal dose range.
A dose of 14.7 mg/kg b.w. represents the NOAEL in the present dog study.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993-09-07 - 1995-02-06
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- once daily a.m. (7 days per week)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 31.6 mg/kg bw/day (nominal)
- Remarks:
- low dose
- Dose / conc.:
- 61.9 mg/kg bw/day (nominal)
- Remarks:
- intermediate dose
- Dose / conc.:
- 121 mg/kg bw/day (nominal)
- Remarks:
- high dose
- No. of animals per sex per dose:
- 15 m
15 f - Control animals:
- yes, concurrent vehicle
- Positive control:
- no
- Observations and examinations performed and frequency:
- Mortality: twice a day (a.m., p.m.)
Behaviour and gen condition of the anomals: daily (occurence of toxicity symptomes)
Food Consumption: Once a week, sarting with pretest period
Body Weight: Once a week, sarting with pretest period
Reflexes (before administration): pain, pinna, coneal reflexes -> once a week, sarting with pretest period
Eye, hearing and dental (before administration): prior to first adminsitration and in test week 4.
Ophthalmological Investigations: prior to first adminstration and in test week 4, all animals of groups 1 + 4, except animals for plasma level determination
Blood Collection: Test weeks 1 + 4, retroorbital venous plexus of one eye, first 10 animals per group
Urine: metabolism cages in test week 4 for 3 hours a.m. from animals selected for blood sampling
Hematology: Test weeks 1 + 4 -> Erythocytes, hematocrit, hemoglobin, leucocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, Trombocytes, differential leucocyte count
Clinical chemistry: Test weeks 1 + 4: ALAT, AKP, ASAT, blood urea; Ca, Cl, CK; creatinine, Gamma-GT, GLDH, iP, K, Na, tot. bili., Chol. tot. protein, triglycerides
Urinalysis: Bili, glucose, hem/erythrocytes, ketones, leucocytes, nitrite, osmolality, pH, protein, urobilinogen, volume
Plasma level: week 4 -> 2, 6, and 24 h after administration - Sacrifice and pathology:
- Anesthesia with CO2, sacrificed by exsanguination
Autopsy: All animals -> full gross necropsy
Organ weights: adrenals (r/l), brain, female genital tract in toto, heart, kidneys (r/l), liver, ovaries (r/l), pituitary, prostate/seminal visicles in toto, spleen, testes (r/l), thymus.
absolute values and relative to b.w. after exsanguination
Histopathology:
Fixation: all organs exept eyes and bone marrow smears -> 10 % formalin
eyes -> SUSA fixative (4 to 16 h), therafter 10 % formalin
bone marrow smears -> air dried
Staining: All fixed organs -> embedding in parafine, sectioned at 4µm, stained with H&E
Add. frozen section of liver tissue -> Oil Red O
Bone marrow smears -> according to PAPPENHEIM - Statistics:
- Mean and SD seperately for each group and sex.
Evaluaion of food consumption, b.w. and organ weighs: DUNNETT-Test
Hematology and clinical chemistry: DUNNETT-Test in case of normal distribution, otherwise STEEL-Test
Significances:
* p < 0.05
** p < 0.01 (according to DUNNETT)
+ p < 0.05 (according to STEEL) - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No changes in low and mid dose.
High dose: 1 male rat showed slight hypokinesia on 3 d in week 4.
Same animal showed coordination disturbances during entire treatment period.
Symptones occuered between 45 and 180 min after administration and lasted up to one day. - Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No changes in low and mid dose.
High dose: Possible substance related changes
Males: Week 1 -> significant decrease of cholesterol until week 4
slight but significant increase of ALAT and GLDH and decrease of tot. protein and triglycerides
Females: Week 4 -> sligtht but significant increases of blood urea and cholesterol - Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Unspecific cliniical symptoms aof an affection of CNS and VNS
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver: male and female rats
Mammary gland - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 61.9 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- histopathology: neoplastic
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 61.9 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Conclusions:
- On the basis of the present 4-week oral toxicity study in Wistar rats it is conducted that the most sensitive organ in the toxicity of alpha-Lipoic acid is the liver. In the last quarter of the treatment period unspecific clinical symptoms of an affection of CNS and VNS were noted. Additionally the mammary gland was affected in a sex specific way.
The severity and incidence of liver findings in the low and mid dose groups indicate an adaptive response to a repeated administration of alpha-Lipoic acid rather than a straight toxic response.
With regard to the absence of changes of other parameters including clinical chemistry the toxicological significance of these findings is equivocal.
Therefore the NOAEL can be assumed at 61.9 mg/kg b.w. alpha-Lipoic acid in male and female Wistar rats. - Executive summary:
The study was performed to gather information o the toxicity profile of alpha-Lipoic acid after repeated daily administration and to assess a NOAEL.
The oral route of administration was chosen because this is the intendet route in man.
Four groups of Wistar rats were used in this study, all containing 15 ale anf female rats each. Five animals per group and sex were exclusively used for blood sampling to ascertain the toxicokinetic profile of the test substance.
Alpha-Lipoic acid was adminstered as a solution in 1,2 -propylene glycol to groups 2, 3 and 4 animals. Group 1 rats recieved 1,2 -propylene glycol as control animals. The dose range was 31.6 mg/kg b.w. as low dose (group 2), 61.9 mg/kg b.w. as intermediate dose (group 3) and 121 mg/kg b.w. as high dose (group 4).
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1968
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.30 (Chronic Toxicity Studies)
- Deviations:
- not specified
- GLP compliance:
- not specified
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Route of administration:
- oral: capsule
- Details on route of administration:
- Diet: ALTROMIN H, 50 g/kg bw. offered daily for an hour (between 8 and 9 a.m.)
Drinking water: ad libitum
Caging: 1 animal per cage, 5 m^2 + 8 m^2
Temperature: 21 +/- 3 °C - Vehicle:
- other: amylum
- Details on oral exposure:
- Administration between 8 and 9 a.m.
- Duration of treatment / exposure:
- 6 month
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- control (IV), sugar capsule
- Dose / conc.:
- 12.5 mg/kg bw/day (nominal)
- Remarks:
- low dose (I)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Remarks:
- intermediate dose (II)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- high dose (III)
- No. of animals per sex per dose:
- 3 m
3 f - Control animals:
- yes
- Observations and examinations performed and frequency:
- Daily: behaviour and general condition
Weekly: b.w.
Hematology
Clinical chemistry
Urinalysis
ECG
Directly before necropsy: examination of eyes (cornea, eye chamber, pupil, lens, vitreous body, eyeground), hearing - Sacrifice and pathology:
- Anesthesia: T61 (0.3 ml/kg b.w.), exsanguination
Gross pathology
Organ weights
Histology (paraffin slices, HE staining): heart, lung, liver, spleen, kidneys, adrenal gland, thymus, hypophysis, gonads, thyroid gland, brain, prostate/uterus, somach, duodenum, jejunum, ileum, colon, rectum, pancreas, eye with optic nerve, bladder, bone marrow, mesenchymals lymph nodes, deferent duct/mamma - Statistics:
- Student-t-Test P <= 0.01
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- > 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- ophthalmological examination
- organ weights and organ / body weight ratios
- urinalysis
- water consumption and compound intake
- Key result
- Critical effects observed:
- no
- Conclusions:
- Under conditions of the study the LOAEL can be expected above 50 mg/kg b.w.
- Executive summary:
In this study the tolerance of alpha-Lipoic acid in beagle dogs was tested. The test item (in an amylum capsule) was administered daily (a.m.) over a period of 6 month.
The daily doses of the test item were 12.5, 25,0 and 50,0 mg/kg b.w.
Contol animals recieved 1 g sucrose / day in a capsule.
None of the dosages showed critical effects.
Behaviour, appearance, feaces, Fodd and water consumption, b.w., hematology, clinical chemimistry, ECG, urinalysis, eyes, set of teeth, gross patholgy and organ weigts gave no hints of intolerance towards the test item.
Histology showed no substance related changes.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1995-07-18 - 1997-12-05
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.30 (Chronic Toxicity Studies)
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age:
Males: 7 weeks
Females: 8 weeks
Body weight
Males: 147 - 188 g
Females: 126 - 170 g
Caging: Macrolon type III
Animals per cage: 1
Bedding: Sterilized animal bedding softwood granulation
Diet: Standard diet ad libitum
Water: Drinking water (Stadtwerke Halle) ad libitum
Room temperaure: 20.4 - 22.6 °C
Relative Humidity: 41 - 68 %
Room Lighting: 6 a.m. - 6 p.m. CET artificial lighting; 6 p.m. - 6 a.m. CET darkness - Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 26 weeks - daily administration
6 weeks recovery - 5 animals of each sex of vehicle group and high dose group - Frequency of treatment:
- once daily between 7 a.m and 1 p.m.; 7 days a week
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- (1) Drinking water
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- (2) Vehicle (1,2-proylene glycol)
- Dose / conc.:
- 21.5 mg/kg bw/day (nominal)
- Remarks:
- (3) low dose
- Dose / conc.:
- 46.4 mg/kg bw/day (nominal)
- Remarks:
- (4) intermediate dose
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- (5) high dose
- No. of animals per sex per dose:
- (1) 10 m + 10 f
(2) 25 m + 25 f (5 animals each for recovery period)
(3) 20 m + 20 f
(4) 20 m + 20 f
(5) 25 m + 25 f (5 animals each for recovery period) - Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Positive control:
- no
- Observations and examinations performed and frequency:
- Mortality: twice daily (a.m. and p.m.)
Behaviour and General Condition: daily
Food Consumption: Once a week
Body Weight: Once a week
Reflexes (before administration)
Eye, Hearing and Dental Examinations (before administration)
Ophthalmological Investigations (before administration) - Sacrifice and pathology:
- Sacifice: CO2 and exanguination
Autopsy
Organ Weights
Histopathology - Other examinations:
- Blood
- Hematology
- clinical chemistry
Urine - Statistics:
- Mean and SD for each group and sex
Food consumption, b.w. and organ weights: DUNNETT-Test
Hematology and clinical chemistry: DUNNETT-Test in case of normal distribution, otherwise STEEL-Test
Significane levels:
- DUNNETT: * p < 0.05; ** p < 0.01
- STEEL: + p < 0.05 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- M + f in high dose group (5)
M of intermediate dose group (4) - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- (2) f: 1 animal spontaneously died
(3) m: 1 animal sacrificed
(5) m: 1 animal spontaneously died; 2 animals sacrificed - Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased liver weigths in mid and high dose males.
Increased spleen weights in high dose males.
Increased absolute liver weigts in high dose females. - Gross pathological findings:
- effects observed, non-treatment-related
- Neuropathological findings:
- not specified
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver of mid and high dose males and high dose females.
Stomach of high dose males and females. - Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 21.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
- mortality
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 46.4 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
- mortality
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 46.4 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 46.4 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Conclusions:
- The dose of 21.5 mg/kg b.w. alpha-Lipoic acid is considered the NOAEL in both males and females during this 26-week oral toxicity study in Wistar rats.
Only minimal findings were present in individual animals at a dose of 46.4 mg/kg b.w. - Executive summary:
On the basis of the present 26-week toxicity study after oral adminstration in Wistar rats it is concluded that alpha-Lipoic Acid induced slight toxic effects on the CNS and VNS at a dose of 100 mg/kg b.w. Only minimal findings were noted in males an 46.4 mg/kg b.w.
A reduction of food consumption was only present in males at mg/kg b.w.; a reduction in b.w. gain was present in both males and females at 100 mg/kg b.w. High dose animals showed slight decreases in red blood cell parameters. Clinical chemistry parameters and measurement of organ weigts indicated the liver as possible target organ of toxicity.
Histopathologicalliy, in the liver increases were noted for microganulomas, basophilia of hepatocellular cytoplasm, polymorphism of periportal hepatocoytes, focal mononuclear cell infiltrates, hepatocellular storage of glycogen observed as hepatocellular rarefication, introcytoplasmatic inclusions and hepatocellular hypertrophy occuring in rats at 100 mg/kg b.w.
Males at 46.4 mg/kg b.w. had increased hepatocellular storage of glycogen and one male of this group had intractoplasmatic inclusions.
Only the intercytoplasmatic inclusions are considered of special toxicological relevance as they may indicate an increased turnover of hepatocytes.
Sings of local irritancy were recorded in the Stomach of high dose group animals.
Predominantly all changes recorded in high dose group animals were reversible during the 6-week recovery peridod.
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01/1971 - 05/1973
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.30 (Chronic Toxicity Studies)
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age: 38 d (m) and 42 d (f)
B.w.: 100 - 105 g
Diet: ALTROMIN R ad libitum
Drinking water: ad libitum
Cages:groups of 3 ro 2 in type III Macrolon cages
Temperature: 24 + 0.5 °C
Rel. humidity: 60 +/- 3 %
Illumination: 12 h a day, intensity 250 Lux - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- (IV) control
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Remarks:
- (I) low dose
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Remarks:
- (II) mid dose
- Dose / conc.:
- 180 mg/kg bw/day (nominal)
- Remarks:
- (III) high dose
- No. of animals per sex per dose:
- (I) + (II): 40 m + 40 f
(III) + (IV): 50 m + 50 f - Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- Behaviour, general condition, food consumption: daily
B.w.: twive a week in first 6 month, intervals of 4 weeks there after.
After 12 and 24 month to the experiment in 10 animals per group and per sex:
Haematology
Clnical chemistry
Urinalysis
Immediately before dissection: eyes (cornea, eye chamber, pupil, lens, vitreous body, eyeground), hearing, teeth - Sacrifice and pathology:
- After 12 month: 10 m + f from (III) and (IV) - decapitation and exsanguination
All the surviving animals were examined at the end or the experiment, and any rat that died in the interim was correspondingly examined after death.
Paraffin sections were prepared from the folling organs for all the animals, and these were then subjected to histological examination with HE-staining:
Heart, lungs, liver, spleen, kidneys, adrenals, thymus, pituitary, gonads, thyroid, brain, prostate/uterus, stomach, duodenum, jejunum, ileum, colon, rectum, salivary gland, eye with optical nerve, urinary bladder, bone marrow, trachea, aorta, oesopagus, pancras, mes. lymph nodes, peripheral nerves, skeletal muscles, tumors - Statistics:
- Student's t test: p <= 0.01
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Mortality rate between 10 % and 25 %
Control and low dose males showed hightest rate. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- High dose: weight gain was inhibited
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Dissection after 12 month: within normal range
Dissection after 24 month: significantly reduced - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Dissection after 12 month: no pathological findings
Dissection after 24 month: changes in color or size - Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- >= 60 - <= 180 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- gross pathology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOAEL
- Effect level:
- >= 20 - <= 60 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- histopathology: neoplastic
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- no
- System:
- other:
- Organ:
- not specified
- Conclusions:
- Under the present experimental conditions, the minimum toxic dose (LOAEL) is probably to be expected between 60 and 180 mg alpha-Lipoic acid/kg b.w./day via the diet.
- Executive summary:
These experiments were carried out in order th investigate the tolerability of alpha-Lipoic acid on oral administration for 2 years to 260 Sprague-Dawley rats. Another 100 animals served as controls. 10 m and 10 f each from the high dose group and from the control group were subjected to an interim dissection after one year of the experiment.
The dose given were 20, 60 or 180 mg alpha-Lipoic acid/kg b.w. a day via the diet. The control rats remain untreated.
At the lower doses (20 and 60 mg/kg b.w.) there were no unambigous indications of any lesions. The finding of a significantly reduced adrenal weight is probably an incidential deviation. The age-related mortality rate, 19 % and 14 %, respectively, was lower than that of the control animals (24 %). At both doses the tumor rate was 25 %, as compared to about 29 % in the control rats.
At the maximum dose (180 mg/kg b.w.) the b.w. was significantly reduced and food consumption paralleled the weight development. Evidently as a consequence of the emaciation the absolute organ weigthts were often reduced, while the relative organ weigts were slightly higher.
Again the mortality was normal for this age. The mortality rate, 13 %, was lower than the corresponding control value of 24 %, and the tumor rate of 30 % did not differ considerably from that in the control group, were it was 29 %.
Behaviour and appearance of these animals, faeces, consumption of water, haematology and clinical chemistry, composition of urine and the checks of hearing, vison and teeth did not provide any unambigous evidence of intolerance reactions at any of the doses tested. The symptoms preciding death and the gross-pathological changes observed during dissection were the same in the test and control animals.
Histological examination after death and after 2 years of administration of any doses tested confirmed the gross-pathological findings. Pathological changes were predominantly observed in heart, lungs, liver, spleen, kidneys, gonads and lymph nodes, and also in the salivary gland, but were less frequent than in the other organs. Their number, nature and extent did not differ markedly between the individual alpha-Lipoic acid doses or between treated and untreated animals. The same applies to tumors wich were also found to about the same extend in each 4 groups.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 14.7 mg/kg bw/day
- Study duration:
- subacute
- Species:
- dog
- System:
- hepatobiliary
- Organ:
- liver
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
Alpha-Lipoic acid is not classified as specific organ toxic.
All gross-pathological and histological findings were either not considered treatment related, not critical or not statistically significant from the control group.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.