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EC number: 271-678-5 | CAS number: 68603-87-2
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
- Principles of method if other than guideline:
- AGS mixtures were administered in a single oral dose to SD rats. Animals were sacrificed 6, 18 or 30 h after treatment. A positive control group was included (Cyclophosphamide). 2 hours before scheduled sacrifice animals were administered colchicine at to arrest cells in metaphase. Animals were sacrificed and both femurs were removed from each animal and metaphase slides were prepared. Slides were stained, coded and scored for chromosomal aberrations (50 metaphase bone marrow cells/animal were evaluated.
- GLP compliance:
- yes
- Type of assay:
- chromosome aberration assay
Test material
- Reference substance name:
- Carboxylic acids, di-, C4-6
- EC Number:
- 271-678-5
- EC Name:
- Carboxylic acids, di-, C4-6
- Cas Number:
- 68603-87-2
- Molecular formula:
- C5H8O4, C4H6O4, C6H10O4
- IUPAC Name:
- Carboxylic acids, C4-6 di-
- Details on test material:
- Adipic acid: 6-9%
Glutaic acid 30-35%
Succinic acid 8-11%
Nitric acid 0.5 - 3%
Lot: FIT-85-45,46,47; white solid powder
Constituent 1
- Specific details on test material used for the study:
- test material: AGS mixture was used as a 50% aqueous solution.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- breeder: Charles River Lab., Wilmington, Massachsusetts
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- body weight at randomization. 239-264 g for males and 178-208 g for females
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- deionized water
- Details on exposure:
- all animals were fasted overnight prior to treatment; AGS mixture (50% aqueous solution), solvent or positive controls were administered as single oral doses at 5 mL/kg bw.
2 to 3 hours prior to sacrifice each animal was given a single intraperitoneal dose of colchicine at 4 mg/kg bw to arrest dividing cells in metaphase. Colchicine was dosed at 10 mL/kg bw and was prepared in distilled water.
Justification for doses:
AGS mixture (50%) was evaluated in a preliminary study at doses of 1375, 2750 and 5500 mg/kg bw. Due to the mortality and pharmacotoxic signs observed at 5500 mg/kg bw for males and 2750 mg/kg bw for females, doses selected for evaluation in the Metaphase Analysis Assay were 2750 mg/kg bw for males and 1375 mg/kg bw for females as an estimation of the maximum tolerated dose.
5500 mg/kg bw: both treated females died within four hours post dosing; one male died 24 hours post dosing and the other exhibited severe pharmacotoxic signs through day 7
2750 mg/kg bw: one female died 24 hours post dosing and the second female died by day 3; both males survived the treatment and exhibited mild to severe pharmacotoxic signs through day 7
Additional tests with higher dilutions (same doses) showed similar effects. - Duration of treatment / exposure:
- 6, 18, 30 h
- Frequency of treatment:
- single treatment
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 375 mg/kg bw (total dose)
- Remarks:
- dose for females, sacrifice 6, 18, and 30 hours after treatment
- Dose / conc.:
- 2 750 mg/kg bw (total dose)
- Remarks:
- dose for males, sacrifice 6, 18, and 30 hours after treatment
- No. of animals per sex per dose:
- vehicle control (water): 7 males and 5 females (6 hour treatment), 5 males and 5 females (each 18 hour and 30 hour treatment)
AGS mixture (50%), 2750 mg/kg bw: 8 males (6 hour treatment), 5 males (each 18 hour and 30 hour treatment)
AGS mixture (50%): 1375 mg/kg bw: 5 females (each 6, 18 hour and 30 hour treatment)
Cyclophosphamide: 20 mg/kg bw: 5 males and 5 females (18 hour treatment) - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Route of administration: oral gavage
- Doses / concentrations: 20 mg/kg bw
Examinations
- Tissues and cell types examined:
- Animals were sacrificed and both femurs were removed from each animal and metaphase slides were prepared.
A total of 500 well spread metaphase cells with a minimum of
overlapping chromosomes, were scored for the presence of chromosome aberration
per experimental treatment point (50 per animal) by two investigators (25 each
per animal). A total of 600 metaphases (12 animals) were scored the 6 hour
solvent control group. Cells were located by systematic searching of the
slide under low power (20X-40X) magnification. Cells judged acceptable for
analysis based on cell morphology and total chromosome nurnber (± 2 of the
normal diploid no. of 42) were then further analyzed with lOOX oil immersion
objective where abnormalities were detected and classified. Vernier
coordinates were recorded for the first and last metaphase scored, as well as
for any abnormal rnetaphases (including gaps) observed. The centromere number
was recorded on all cells analyzed. - Evaluation criteria:
- Cytogenetic abnormalities were classified on a standard
scoring sheet according to chromosome or chromatid aberrations and further
according to type of aberration (see Legend on page 12). Aberrations were
classified according to the nomenclature cf Buckton and Evans, 1973 and
Savage, 1975. - Statistics:
- Mean aberrations per cell per rat (50 cells per rat)
were analyzed for statistically significant increases in chromosome aberration
by one-tailed t tests. Each treatment group was analyzed separately as
compared to its concurrent negative control group. The mean and standard
deviation of aberrations/cell were also determined for each group of rats (500
cells~ 50 cells per rat). The number of aberrant metaphases was analyzed by
Chi-square analysis for statistically significant increases. Statistical
significance was determined at the p >= 0.05 probability level.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- death in high dose group
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- Doses selected for evaluation in the Metaphase Analysis Assay were 2750 mg/kg bw for males and 1375 mg/kg bw for females as an estimation of the maximum tolerated dose.
General toxicity in the main assay:
Three males died before sacrifice; most of the remaining males and females had decreased body tone and activity, body drop, abnormal gait, ptosis and piloerection. In addition, some animals had tremors and vocalization on touch.
6 Hour Group - (observed approximately 4 hours after dosing):
One male was dead before colchicine administration. The remaining males had decreased body tone and activity, body drop, abnormal gait, ptosis and piloerection. In addition, two males bad tremors. All females showed bad decreased body tone, piloerection and vocalization on touch. A second male died before harvest. The sponsor was notified and requested that 5 extra male rats be dosed, two with the solvent control and the other three with AGS mixture (50%) at 2750 mg/kg to ensure two available rats to replace the dead ones. One male died before colchicine administration. The other two males exhibited moderate pharmacotoxic signs.
18 Hour Group - (observed approximately 16 hours after dosing):
All rats had piloerection. Three males and three females also had decreased body tone. Four males and three fernales made vocalizations when touched. One male bad abnormal gait and one female abnormal stance.
30 Hour Group - (observed approximately 28 hours after dosing):
All rats had decreased body tone and piloerection. All males had abnormal stance. One male and two females made vocalizations when touched. Two fernales had body drop.
Any other information on results incl. tables
No statistically significant increase in the incidence of aberrations or the number of cells with one or more aberrations were observed in the animals treated with dicarboxylic acid mixture at any dose and at any of the three sampling time points. (see Table 1 and attachment)
Table 1: in vivo bone marrow cytogenetics - proportion of cells with one ore more aberrations
compound | dose (mg/kg bw) | harvest time (hrs) | sex | no. of rats | no. of cells with one or more aberrations | no. of normal cells | % aberrant cells/group |
water | 5 mL/kg bw | 6 | M | 7 | 1 | 349 | 0.3 |
water | 5 mL/kg bw | 6 | F | 5 | 1 | 249 | 0.4 |
AGS mix (50%) | 2750 | 6 | M | 5 | 1 | 249 | 0.4 |
AGS mix (50%) | 1375 | 6 | F | 5 | 0 | 250 | 0.0 |
water | 5 mL/kg bw | 18 | M | 5 | 2 | 248 | 0.8 |
water | 5 mL/kg bw | 18 | F | 5 | 4 | 246 | 1.6 |
AGS mix (50%) | 2750 | 18 | M | 5 | 1 | 249 | 0.4 |
AGS mix (50%) | 1375 | 18 | F | 5 | 0 | 250 | 0.0 |
cyclophosphamide | 20 | 18 | M | 5 | 123 | 127 | 49.2** |
cyclophosphamide | 20 | 18 | F | 5 | 128 | 122 | 51.2** |
water | 5 mL/kg bw | 30 | M | 5 | 0 | 250 | 0.0 |
water | 5 mL/kg bw | 30 | F | 5 | 1 | 249 | 0.4 |
AGS mix (50%) | 2750 | 30 | M | 5 | 2 | 248 | 0.8 |
AGS mix (50%) | 1375 | 30 | F | 5 | 1 | 249 | 0.4 |
** significant in Chi-square at p >= 0.01
Applicant's summary and conclusion
- Executive summary:
The potential of dicarboxylic acid mixture (50%) to induce structural chromosomal aberrations in the hemopoetic cells of the rat bone marrow were investigated in vivo after oral gavage. Dicarboxylic acid mixture (2750 mg/kg bw for males and 1375 mg/kg bw for females) was administered in single oral doses to SD rats and animals were sacrificed 6, 18 and 30 hours after dosing. A positive control group (cyclophosophamide; 20 mg/kg) was sacrificed at the 18 hours time point. 2 Hours before sacrifice animals were administered with colchinine to arrest cells in metaphase. Both femurs were removed from each animal and metaphase slides were prepared. A total of 50 metaphase cells were analysed for each animal for the presence of chromatid and chromosome type aberrations. The positive control group resulted in a significant increase in chromosomal aberrations.
Two rats dosed with 2750 mg/kg died. The surviving animals in all test groups exhibited from mild to severe pharmacotoxic signs and the authors concluded that the test item was evaluated at or near the MTD. No statistically significant increase in the incidence of aberrations or the number of cells with one or more aberrations were observed in the animals treated with dicarboxylic acid mixture at any dose and at any of the three sampling time points. Therefore, in vivo the test item was not clastogenic to hempoietic cells of the rat bone marrow.
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