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EC number: 946-155-6 | CAS number: -
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2010
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- Non-GLP (Winonlin software was not validated), guideline study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
- Objective of study:
- toxicokinetics
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
- Deviations:
- no
- GLP compliance:
- no
Test material
- Reference substance name:
- Reference substance 001
- EC Number:
- 700-073-5
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratoires France, Domaine des Oncins, 69592 L’Arbresle Cedex, France
- Age at study initiation: 6 to 10 weeks
- Weight at study initiation: males 237.1 - 273.8 g, females 142.9 - 182.0 g
- Housing: Animals were housed in groups (separated by sex) in cages of standard dimensions with sawdust bedding (or equivalent).
- Diet: RM1 (E)-SQC SDS/DIETEX feed (quality controlled/irridiation sterilised) was available ad libitum except during fasting experimental periods.
- Water: Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple.
- Acclimation period: minimum of 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 – 24
- Humidity (%): 45 – 65
- Air changes (per hr): 10
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Doses of test item were expressed in g/kg of DEI (Di-ester-isosorbide) and were adjusted on the basis of the most recent body weight. A correction factor of 1.15 was used (1 g of LAB 3822 contains 87 % of DEI).
Animals received the following volumes:
- group 1 (0 g/kg bw of DEI): 2.35 mL/kg bw
- group 2 (0.5 g/kg bw of DEI): 0.59 mL/kg bw
- group 3 (1 g/kg bw of DEI): 1.17 mL/kg bw
- group 4 (2 g/kg bw of DEI): 2.35 mL/kg bw - Duration and frequency of treatment / exposure:
- daily for 91 consecutive days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 575 mg/kg bw (total dose)
- Remarks:
- test substance dissolved in water
- Dose / conc.:
- 1 150 mg/kg bw (total dose)
- Remarks:
- tets substance dissolved in water
- Dose / conc.:
- 2 300 mg/kg bw (total dose)
- Remarks:
- test substance dissolved in water
- Dose / conc.:
- 500 mg/kg bw (total dose)
- Remarks:
- mg/kg bw of the active ingredient (DEI)
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- mg/kg bw of the active ingredient (DEI)
- Dose / conc.:
- 2 000 mg/kg bw (total dose)
- Remarks:
- mg/kg bw of the active ingredient (DEI)
- No. of animals per sex per dose / concentration:
- - Control group: 3
- Test groups: 9 - Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Proposed doses selected are based on previous studies (Repeated dose 28-day toxicity study in the rat by the oral route followed by a 14-day drug withdrawal period, CERB REPORT No. 20070263TRB) and on the presumed effective pharmacological dose. The highest dose should reveal signs of toxicity and the lowest dose should represent a no-observed-adverse effect level (NOAEL).
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling - test groups: D1 (before dosing and at 30 min, 1 h, 2 h, 4 h and 8 h post-dose) on D28 at pre-dose and on D91 (before dosing and at 30 min, 1 h, 2 h, 4 h and 8 h post-dose)
- Time and frequency of sampling - control group: D1 (before dosing and at 2 hours post-dose) on D28 at pre-dose and on D91 (before dosing and at 2 hours post-dose).
- After oral administration, the hypothesis is made that the DEI is hydrolysed by the pancreatic's lipase. This hydrolysis split DEI into Isosorbide and free fatty acids. Consequently, the assay of Isosorbide in plasma could be used as a marker of the exposure to the LAB 3822.
- Other: Three males and three females were sampled per time point. - Statistics:
- Toxicokinetic parameters were evaluated by non compartmental modeling from mean plasma concentrations of the test substance achieved after dosing by the oral route at each dose level, using Winonlin software.
Results and discussion
Toxicokinetic / pharmacokinetic studies
Toxicokinetic parameters
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 2.09 to 4.56 h
Metabolite characterisation studies
- Metabolites identified:
- no
Bioaccessibility (or Bioavailability)
- Bioaccessibility (or Bioavailability) testing results:
- The half-life was found between 2.09 to 4.65 hours. Comparison of exposure (AUClast) in males and females suggested that the males were slightly more exposed than the females (ratio between 1.14 at 1 g of DEI/kg on D91 to 1.55 at 1 g of DEI/kg on D1). Furthermore, AUClast increased with the dose level and were comparable between D1 and D91 (ratio AUClast D91/D1 between 0.76 and 1.08). There was a good linearity between exposure or Cmax and the dose levels.
Any other information on results incl. tables
Dosing |
Sex |
Day |
T1/2 (h) |
Tmax (h) |
Cmax (µg/mL) |
Cmax/dose (kg*µg/mL/g) |
AUClast (h*µg/mL) |
AUClast/dose (kg*h*µg/mL/g) |
0.5 g of DEI/kg |
M |
1 |
3.99 |
1 |
204.96 |
409.920 |
937.33 |
1874.66 |
0.5 g of DEI/kg |
F |
1 |
2.25 |
1 |
211.34 |
422.680 |
687.15 |
1374.29 |
0.5 g of DEI/kg |
M |
91 |
2.76 |
1 |
206.80 |
413.600 |
924.99 |
1849.97 |
0.5 g of DEI/kg |
F |
91 |
2.30 |
1 |
200.51 |
401.020 |
743.77 |
1487.53 |
1 g of DEI/kg |
M |
1 |
3.27 |
1 |
368.08 |
368.080 |
1870.48 |
1870.48 |
1 g of DEI/kg |
F |
1 |
2.09 |
1 |
367.97 |
367.970 |
1208.38 |
1208.38 |
1 g of DEI/kg |
M |
91 |
3.16 |
2 |
322.18 |
322.180 |
1427.30 |
1427.30 |
1 g of DEI/kg |
F |
91 |
4.65 |
1 |
325.51 |
325.510 |
1255.79 |
1255.79 |
2 g of DEI/kg |
M |
1 |
3.31 |
2 |
654.61 |
327.305 |
3089.45 |
1544.73 |
2 g of DEI/kg |
F |
1 |
2.35 |
2 |
542.13 |
271.065 |
2304.52 |
1152.26 |
2 g of DEI/kg |
M |
91 |
3.40 |
2 |
498.96 |
249.480 |
2879.04 |
1439.52 |
2 g of DEI/kg |
F |
91 |
2.48 |
2 |
507.94 |
253.970 |
2061.12 |
1030.56 |
Applicant's summary and conclusion
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.