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EC number: 807-840-4 | CAS number: 64896-70-4
- 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
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- 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
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- Endpoint summary
- Stability
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- 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
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- Terrestrial toxicity
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- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Genetic toxicity
- Carcinogenicity
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- Specific investigations
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- Additional toxicological data

Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: other: Genotoxic activity using micronucleus in rat
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Study period:
- from 2008-01-28 to 2008-04-24
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: in compliance with OECD and GLP guideline (as the data is used in a read-across approach, a maximal reliability score of 2 was attributed).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- Automatically generated during migration to IUCLID 6, no data available
- IUPAC Name:
- Automatically generated during migration to IUCLID 6, no data available
- Details on test material:
- SPONSOR : ROQUETTE
TEST ITEM : LAB3822
BATCH NUMBER : FAL 07/25
I.P.L. REGISTRATION NUMBER : 070713
EXPIRY DATE : March 2009
APPEARANCE : slightly yellowish liquid
PURITY* : 87%
DENSITY* : 1.02
STORAGE CONDITIONS : at room temperature
STABILITY UNDER STORAGE CONDITIONS : up to its expiry date (i.e. March 2009)
QUANTITY SUPPLIED : 250 mL
*: A purity and a density correction were made. The doses are expressed in mg/kg of pure LAB3822.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Male and female OFA Sprague Dawley rats (Charles RIVER origin, Saint -Germain-sur-l'Arbresle- FRANCE) are used for the study. The period of acclimatization is at least 5 days. The animals receive a clinical examination in order to retain only the healthy ones.
The animals are housed in polypropylene cages measuring 42,5 x 26,6 x 15 cm, covered by a stainless steel netted lid, in which they are placed in groups of 3 or 2 by random-distribution.
The cages are placed in a ventilated cupboard slightly overpressurized relative to animal room also ventilated.
The bedding consists of dust-free, sterilized wood shavings.
The feedstuff used is No. A04C10 irradiated rat/mouse feed from SAFE batch 70718.
The animals are not fasted at the treatment time. Drinking water softened, treated by osmosis and filtered on 0.2 μm membrane is provided ad libitum.
The temperature in the ventilated animal cupboard is 22 ± 3 °C, and humidity is 55 ± 15 %.
Ventilation renews the air 20 times an hour. A timer provides lighting 12 hours a day (8 a.m. - 8
p.m.) in all the animal rooms.
Animals : rat: OFA Sprague Dawley sex: male and female ; weight: 159 g to 192 g (males); 129 g to 157 g (females) ;
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- None
- Details on exposure:
- After random-distribution, 5 groups of animals OFA Sprague Dawley rats from Charles River (4 groups of 10, and one group of 14, for a total of 27 males and 27 females), weighing approximately 200 g and 5 to 6 weeks old, are used for this test. Ears rings identify animals.
Treatment takes the form of 2 successive administrations at 24-hour intervals by the route specified in the specific study plan. As the test item is administered as supplied, no vehicle is used in the present study and the negative control thus received no treatment (neither solution or suspension).
The reference substance, cyclophosphamide, is administered by the intraperitoneal route in a single injection 24 hours before sampling.
Samples are taken at 24 hours after the last treatment.
The animals are treated according to the experimental program below:
Negative control (no treatment) :5males ; 5 females
Test item: High dose, maximum tolerated dose (MTD) or 2000 mg/kg/day (x2)(If the maximum tolerated dose is equal or higher than 2000 mg/kg, this dose is administered according to OECD (1997) and HAYASHI et al. (2007) : 5(+2) males ; (+2)females (For the group treated with the high dose, 2 animals of each sex are treated, in parallel, but are sacrificed and examined only in case of mortality observed in the five first treated animals.
Test item: Mid dose, MTD/2 or 1000 mg/kg/day (x2) (If the maximum tolerated dose is equal or higher than 2000 mg/kg, this dose is administered according to OECD (1997) and HAYASHI et al. (2007)) : 5males ; 5 females
Test item: Low dose, MTD/4 or 500 mg/kg/day (x2)(If the maximum tolerated dose is equal or higher than 2000 mg/kg, this dose is administered according to OECD (1997) and HAYASHI et al. (2007)) : 5males ; 5 females
Doses / concentrations
- Remarks:
- Doses / Concentrations:
2000 – 1000 – 500 mg/kg/day (x 2)
Basis:
- Control animals:
- yes
- Positive control(s):
- The reference substance is cyclophosphamide
- Route of administration: intraperitoneal
- Doses / concentrations:25mg/kg IP (positive control).The animal treatment with the positive control is realized, only once, after the treatment with the studied test item.
Number of animals : 5 males ; 5 females
Examinations
- Details of tissue and slide preparation:
- At the sampling time, the animals are sacrificed by CO2 asphyxia; the femurs are removed, and the bone marrow is extracted with foetal calf serum (1 mL per animal).
The cell suspensions are centrifuged for 5 minutes at 1000 rpm. The supernatant is eliminated. The centrifugate is spread on slides. The smears are stained using a technique, derived from the May Grunwald Giemsa technique (SCHMID, 1975), which makes it possible to distinguish between polychromatic and normochromatic erythrocytes.
After coding the slides by a person not involved in the study, two slides per animal are read by two independent operators; for each animal, the number of polychromatic erythrocytes having one or more Howell-Jolly bodies (micronuclei) is determined for at least 2000 polychromatic erythrocytes.
(In case of divergence, 2000 new polychromatic erythrocytes are examined; the retained value is the mean of all readings).
The polychromatic/normochromatic erythrocyte ratio is determined by analyzing at least 1000 erythrocytes per animal.
Results and discussion
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
The test item LAB3822 (batch FAL 07/25) was investigated by means of the in vivo micronucleus test in male and female OFA Sprague Dawley rats treated orally with 2000 – 1000 and 500 mg/kg/day (x2), followed by one sampling time 24 hours after the last treatment. As a conclusion, LAB3822 induced no genotoxic activity under these experimental conditions.
Thirty minutes, 2 or 4 hours after oral administration of 500, 1000 or 2000 mg/kg of LAB3822, plasmatic concentrations of Isosorbide measured in OFA Sprague-Dawley rats clearly demonstrated a systemic exposure to Isosorbide, and thus to LAB3822.
(The determination of Isosorbide concentrations in plasma was performed in a GLPcompliant laboratory using a validated analytical method (CERB/Reference No. 20080183B). The dosing results were thus considered as reliable). - Executive summary:
STUDY OF GENOTOXIC ACTIVITY USING THE MICRONUCLEUS TEST IN RAT
(2 treatments, 1 sampling time)
SUMMARY
SPONSOR : ROQUETTE
TEST ITEM : LAB3822
BATCH NUMBER : FAL 07/25
STUDY LOCATION : INSTITUT PASTEUR DE LILLE
Genetic Toxicology Laboratory
1, rue du Professeur Calmette - B.P. 245
59019 LILLE CEDEX
THIS STUDY WAS CARRIED OUT IN COMPLIANCE WITH GOOD LABORATORY PRACTICE REGULATIONS
METHODS
Animals (ex, strain, species) male and female OFA Sprague Dawley rats Number of animals per group 5 males and 5 females Form administered test item administered as supplied Route oral Dose volume test item administered as supplied: the dose volume was dependant on the weight of the rat Vehicle test item administered as supplied Stability in vehicle not applicable Treatment schedule negative control and treated: 2 daily treatments positive control: one treatment Number of sampling times 1: negative control and treated: 24 hours after the last treatment 1: positive control: 24 hours after treatment TOXICITY ASSAY
In accordance with the Amendment No. 1, no preliminary toxicity assay was performed. Indeed, previous acute toxicity study by oral route (CERB study number 20070258 TR) demonstrated that the DMT was higher than 2000 mg/kg in male and female Sprague Dawley rats. The genotoxicity assay was thus performed at 2000 – 1000 and 500 mg/kg/day (x2). No clinical signs were observed during the mean genotoxicity assay.
GENOTOXICITY ASSAY
Number of sampling times 1: negative control and treated: 24 hours after the second treatment 1: positive control: 24 hours after single treatment Reference substance cyclophosphamide, 25 mg/kg, intraperitoneal Number of polychromatic erythrocytes observed for each animal 2000 RESULTS:
Genotoxicity assay
Number of sampling times : 1: negative control and treated: 24 hours after the second treatment
1: positive control: 24 hours after single treatment
Reference substance
Number of polychromatic erythrocytes observed for each animal: 200
SAMPLING TIME(24 h after last treatment) TEST ITEMDOSES in mg/kg/day (x2) SEX PCE/NCE RATIO MICRONUCLEI FOR 1000 PCE Mean Student's t Test (p) Mean Mann Whitney(p) Negative control Group VEHICLE M 1.38 0.70 F 1.01 0.40 M+F 1.20 0.55 Positive control Group Cyclophosphamide25 mg/kg/day (x1) M 0.72 <0.05 7.60 p<0.01 F 0.60 <0.05 6.60 p<0.01 M+F 0.66 <0.001 7.10 p<0.001 LAB 3822TREATEDGROUPS 2000 M 1.04 N.S. 0.80 N.S. F 1.21 N.S. 0.90 N.S. M+F 1.12 N.S. 0.85 N.S. 1000 M 0.93 N.S. 0.60 N.S. F 0.94 N.S. 0.30 N.S. M+F 0.93 N.S. 0.45 N.S. 500 M 1.06 N.S. 0.20 p<0.05 F 0.89 N.S. 0.20 N.S. M+F 0.97 N .S. 0.20 p<0.05 No statistically significant increase in the number of micronuclei was noted in male and in female rats dosed with 2000 - 1000 and 500 mg/kg/day (x2).
CONCLUSION:
The test item LAB3822 (batch FAL 07/25) provided by ROQUETTE was investigated by means of the in vivo micronucleus test in male and female OFA Sprague Dawley rats treated orally with 2000 – 1000 and 500 mg/kg/day (x2), followed by one sampling time 24 hours after the last treatment. As a conclusion, LAB3822 induced no genotoxic activity under these experimental conditions.
Thirty minutes, 2 or 4 hours after oral administration of 500, 1000 or 2000 mg/kg of LAB3822, plasmatic concentrations of Isosorbide measured in OFA Sprague-Dawley rats clearly demonstrated a systemic exposure to Isosorbide, and thus to LAB3822. (The determination of Isosorbide concentrations in plasma was performed in a GLP-compliant laboratory using a validated analytical method (CERB/Reference No. 20080183B). The dosing results were thus considered as reliable).
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