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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
Repeated dose toxicity: oral
Administrative data
- 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.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1995
Materials and methods
Test guideline
- 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
Test material
- Reference substance name:
- 5-(dithiolan-3-yl)valeric acid
- EC Number:
- 214-071-2
- EC Name:
- 5-(dithiolan-3-yl)valeric acid
- Cas Number:
- 1077-28-7
- Molecular formula:
- C8H14O2S2
- IUPAC Name:
- 5-(1,2-dithiolan-3-yl)pentanoic acid
- Reference substance name:
- unknown
- IUPAC Name:
- unknown
- Reference substance name:
- Water
- EC Number:
- 231-791-2
- EC Name:
- Water
- Cas Number:
- 7732-18-5
- Molecular formula:
- H2O
- IUPAC Name:
- dihydrogen oxide
- Test material form:
- solid: bulk
- Details on test material:
- This composition is the usual techical grade of AlzChem AG. It will be used when test substance has this composition (or is very closed) or no specific information is available
Constituent 1
impurity 1
impurity 2
Test animals
- 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
Administration / exposure
- 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.)
Doses / concentrationsopen allclose all
- 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
Examinations
- 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
Results and discussion
Results of examinations
- 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
Effect levels
open allclose all
- 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
Target system / organ toxicity
open allclose all
- 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
Applicant's summary and conclusion
- 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.
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