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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: other routes
Administrative data
- Endpoint:
- short-term repeated dose toxicity: other route
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1994-04-18 - 1995-03-16
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study ower prepared study while seeking authorisation of the substance as active incredient for medical treatment.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Comission Directive No. 91/507/EEC Council Recommendation No. 83/571/EEC
- 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 9 month, f 9 month
B.w. m 10.8 - 14.4 kg, f 10.2 - 13.0 kg
Caging: Boxes 6.0 m x 1.2 m
No of animals per box: 1 or 2 (group 2 - 4), 3 (group 1)
Diet: Standard dog diet ad libitum
Water: ad libitum in drinking water quality
Room temperature: 24 - 26 °C
Relative humidity: 21 - 49 %
Lighting: 6 a.m. - 6 p.m. artificial lighting, 6 p.m. - 6 a.m.natual dark rhythm
Administration / exposure
- Route of administration:
- intravenous
- Vehicle:
- water
- Remarks:
- NaCl 0.9 %
- Details on exposure:
- Before and after test substance administration approx. 1 ml physiological saline solution (0.9 %) were injected via three-way valve.
Duration of injection approx 1 min. - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- Daily a.m. (7 days a week)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- control
- Dose / conc.:
- 6.81 mg/kg bw/day (nominal)
- Remarks:
- low dose
- Dose / conc.:
- 9.09 mg/kg bw/day (nominal)
- Remarks:
- intermediate dose
- Dose / conc.:
- 12.1 mg/kg bw/day (nominal)
- Remarks:
- high dose
- 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):
- Low dose: Males -> diarreha and vomitus, one day in week 1
Females -> slight to moderate swellings of front legs during single days of treatment
Intermediate dose: Males -> diarreha during one day in week 3, one dog showed slight swelling of the front legsduring several days of the treating period
Females -> vomitus was noted one day in week 2 + 4, slight swelling of the front legs during single days
High dose: Males -> diarreha during one day in week 3, one animal showed vomitus during first day of treatment. Slight swelling of front legs during several days. One male showed skin reddening during three days of treatment.
Females -> vomitus in two animals during one day of week 2 and in one animal during one day in week 4. - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant decrease in platelets was noted in low dose females during week 1 exmination.
During Week 4 in females the number of white blood cells (WBC) das decreased in treated animals compared to controls. No dose dependency. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Slightly increased glucose levels, 15 min after administration and more increased after 60 min in males and females. No statistical significance.
Males in group 4: Statistically significant increased Tot. Prot. in week 4
Females in group 4: Statistically significant increased Tot. Prot. in week 1 + 4, slightly but statistically significant increased ALAT in week 4
Males in group 2: increased AKP in week 4,
Males in group 3: decrease of Tot. Bili. in weekt 4
Males in group 2 + 3: decreased Na in week 4
Females in group 2: decreased CK in week 4
Not dose related, not reflecting toxic effect. - Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Oral beningn papillomas in animals Nos. 12 and 18
Application site was thickend and/or had perivascular hemorrhages in many animals in all dose groups including control animals. => Traumatic character of daily i.v. injections. - Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Kidneys showed a maginally higher severity of minimal to mild focal mineralization in some treated animals, especially females. No dose response relationship.
Injection sites showed inflammatory changes and hemorrhages. => Traumatic character of daily i.v. injections.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 9.09 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 12.1 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 9.09 mg/kg bw/day (nominal)
Applicant's summary and conclusion
- Conclusions:
- On the basis of the present 4-week toxicity study after daily i.v. administration in Beagle dogs it is concluded that alpha-Lipoic acid induced no specific toxic effects up to 12.1 mg/kg b.w.
As known from dose-range-finding studies, only slightly higher doses would have led to severe toxicity with even risk of deaths.
Diarrhea and/or vomitus, wich were present in single test substance treated animals during single days of the treatment period of the present study, are more considered to be incidental findings than to reflect a toxic effect. - Executive summary:
Under the assumption, that the findings of diarrhea and/or vomitus in single test substance treated animals during only single days of the treatment period are of no toxicological relevance, the dosage of 9.09 mg/kg b.w. is considered the NOEL in males and females during this 4 -week toxicity study after daily intravenous administration in beagle dogs.
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