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EC number: 294-620-0 | CAS number: 91744-56-8
- 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
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Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- Neurobehavioural examination was not performed.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 6106-21-4
- Cas Number:
- 6106-21-4
- IUPAC Name:
- 6106-21-4
- Details on test material:
- - Name of test material (as cited in study report): Butanedioic acid, disodium salt, hexahydrate
- Physical state: White crystalline
- Analytical purity: 99.9 wt%
- Stability under test conditions: Verified after exposure
- Storage condition of test material: in cool and dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: CD(SD)IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
- Age at study initiation: (P) 10 wks
- Weight at study initiation: (P) Males: 343 - 408 g; Females: 209 - 247 g
- Fasting period before study: No
- Housing: for males and non-preganant females: individual in stainless steel cages
- Diet (e.g. ad libitum): NMF, pelleted, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 - 25.6 °C
- Humidity (%): 42 - 74%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: injection solvent
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared more than once in 6 days. Stability of dosing solution (3 and 200 mg/mL) was verified for 24 hours at 24 °C and for 7 days at 4°C.Test item was diluted in injection water.
VEHICLE
- Lot/batch no. (if required): A005CS - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: max. 4 days
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): Day 18 of gestation until day 4 of lactation: individual in plastic tray with wood chips - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- At the study initiation, dosing solutions were analyzed and actual concentrations were 91.9 - 98.3% of nominal concentration.
- Duration of treatment / exposure:
- Male: 14 days before mating, 14 days during mating, 24 days after mating
Females in mating groups: 14 days before mating, 1 - 4 days during mating, 22 or 23 days during resulting pregnancies, 4 days during lactation (total 42 - 46 days) - Frequency of treatment:
- daily, 7 days/week
- Details on study schedule:
- - Age at mating of the mated animals in the study: 12 weeks
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg b.w./day
Basis:
nominal conc.
- No. of animals per sex per dose:
- 6
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were based on the results of a foregoing range finding study, in which animals were orally exposed to 0, 30, 100, 300 and 1000 mg/kg bw/day for 14 days (published year unknown, 4802(115-144)). No marked changes were observed even in 1000 mg/kg bw/day group. Therefore, 100, 300 and 1000 were selected as the dose levels for the main study.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day during administration period, and once before necropsy
BODY WEIGHT: Yes
- Time schedule for examinations: males: Day 1, 8, 15, 22, 29, 36, 43, 50 and 53
females: Day 1, 8, 15 before mating, Day 0, 7, 14 and 20 during gestation, Day 0, 4 and 5 during lactation
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day after last administration (Day 53 of males, Day 5 of lactation of females)
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all administered animals
- Parameters checked: WBC, RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, Platelets, Reticulocytes, PT, APTT, Fibrinogen, Differential leukocytes: Lymphocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Large unstained cells
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day after last administration or day 15 of recovery period
- Animals fasted: Yes
- How many animals: all administered animals
- Parameters checked: T-potein, Albumin, A/G, Glucose, T-cholesterol, Triglycerides, BUN, Creatinine, T-bilirubin, AST, ALT, ALP, Na, K, Cl, Ca, Inorganic-P, Total bile acid
URINALYSIS: Yes
- Time schedule for collection of urine: In the last week of administration period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked: Volume, Color, pH, Occult blood, Glucose, Protein, Osmotic pressure - Oestrous cyclicity (parental animals):
- Estrous cycle length and normality were evaluated in females by vaginal smears prior to mating, and optionally during mating, until evidence of mating was found.
- Sperm parameters (parental animals):
- Parameters examined in [all/P/F1/F2] male parental generations:
testis weight, epididymis weight, cell type and number per Sertoli cell in seminiferous tubules - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals on the day after last administration
- Maternal animals: All surviving animals on Day 5 of lactation
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Histopathology: Skin, heart, lung, trachea, liver, pancreas, esophagus, stomach, duodenum, Payer's patch, colon, small intestine, thymus, spleen, mandibular lymph node, mesenteric lymph node, kidney, urinary bladder, testis, epididymis, ventral prostate, seminal vesicle, piruitary, thyroid, parathyroid, cerebrum, cerebellum, pons, eyeball, sternal bone, femoral bone, sternal bone marrow, femoral bone marrow, spinal cord (sternal, cervical and lumber), mammary gland, sciatic nerve, tongue, ovary, uterus and vagina.
Organ weight: Brain, thymus, liver, spleen, kidneys, adrenals, testes, epididymides, and ovaries. - Postmortem examinations (offspring):
- SACRIFICE
- Day 5 of lactation
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- Barlett test, Dunnett test, Steel test, Fisher test
- Reproductive indices:
- - Copulation index: (number of pairs with successful copulations/number of pairs)x100
- Fertility index: (number of pregnant females/number of pairs with successful copulation)x100
- Implantation index: (number of implantation scars/number of corpora lutea)x100
- Gestation index: (number of dams having live pups/number of pregnant dams)x100
- Delivery index: (number of pups born/number of implantation scars)x100
- Birth index: (number of live pups born/ number of implantation scars)x100 - Offspring viability indices:
- - Sex ratio at birth: (number of male pups/number of female pups
- Viability index: (number of live pups on Day 4 of lactation/number of live pups born)x100
Results and discussion
Results: P0 (first parental generation)
Details on results (P0)
No mortality was observed in all groups. Loose stool was observed in one male in 100 mg/kg, four males in 1000 mg/kg and one female in 1000 mg/kg group. Changes in 1000 mg/kg was regarded as test compound related effect. However, the changes in one male in 100 and one female in 1000 mg/kg occurred accidentally. Loss of hair was observed in two males of 300 mg/kg, three males of 1000 mg/kg and several females in all groups including control group. Crust was observed in one male in 300 mg/kg, two males in 1000 mg/kg, one female in 100 mg/kg and one female in 1000 mg/kg. Discharge of eye was observed in one male in 300 mg/kg, one male in 1000 mg/kg. Nasal discharge was observed in two males of 300 mg/kg and two males of 1000 mg/kg. Salivation was observed in one male in 1000 mg/kg and one female in 1000 mg/kg. These changes were not tox effects by the test item since these were seen sometimes also in control group.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No changes were detected.
HEMATOLOGY (PARENTAL ANIMALS)
No changes were detected.
BLOOD CHEMISTRY (PARENTAL ANIMALS)
Increased sodium was observed in males of 300 and 1000 mg/kg. This change was seemed to be derived by sodium ion of test substance. Therefore, this was not tox effect. Chloride was increased in 300 mg/kg but not marked change. Total bile acid was decreased in males of 1000 mg/kg. This change was caused by quite variable values in the control group. Values in 1000 mg/kg were within scatter ratio of control group. Creatinine was increased in females of 300 mg/kg. This was not tox effect of the test item due to lack of dose-responsibility. BUN was increased in females of 1000 mg/kg. Test item may effect on kidney function.
URIANALYSIS (PARENTAL ANIMALS)
One male showed marked and mild occult blood in 1000 mg/kg and 300 mg/kg, respectively. The relationship between this change and test item was not clear. One male and two males showed higher protein (more than 300 mg/dL) in 300 and 1000 mg/kg, respectively. Test item may effect on kidney function. However, no changes were detected by histopathological findings in kidneys.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
One female showed the irregular estrous cycle in 100 and 1000 mg/kg. However, no changes were found in the frequency of irregula cycle occurance.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No changes were observed between administred groups and control group.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Duration of gestation was decreased in 100 and 1000 mg/kg. This change was slight and not caused by the test item since all animals showed the normal duration (22 or 23 days).
ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute weight of adrenals was increased in males of 1000 mg/kg. This change was not regarded as tox effect since no histopahological changes were detected and relative weight was not significantly difference.
No changes were found in females in administered groups and control group.
GROSS PATHOLOGY (PARENTAL ANIMALS)
Diverticulum of small intestine was observed in one male of 1000 mg/kg, red patch/zone of liver in one male of 300 mg/kg, white patch/zone of liver in one male of 1000 mg/kg, enlarged testis in one male of 1000 mg/kg and nodule of epididymis. No changes were regarded as compound-related effect.
Adhesion of spleen was observed in one female of control group. Two females and one female showed black patch in stomach in 300 mg/kg and 1000 mg/kg, respectively. Cyst of pituitary gland was observed in one female of 1000 mg/kg and thin hair in one female of 1000 mg/kg. These changes were also not regarded as compound-related effect.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Dilatation of seminiferous tubule was observed in one male in 1000 mg/kg. This change was not regarded as compound-related effect, since no changes were found in sperm cycle. Atrophy of seminiferous tubule was observed in one male in 300 mg/kg. This change was also not regarded as tox effect because no change was found in higher dosing group.
Necrosis of stomach was observed in females in 300 and 1000 mg/kg. This change was not observed in males. Therefore, this change occurred naturally due to stress of gestation and delivery.
Necrosis of liver and microgranuloma was observed in administered males and females. These changes were not caused by the test item since no dose-responsibility was found and these change are observed naturally.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- (fertility)
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects on reproduction parameters
- Dose descriptor:
- NOAEL
- Remarks:
- (paternal)
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects on reproduction parameters
- Dose descriptor:
- NOAEL
- Remarks:
- (maternal)
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects on reproduction parameters
Results: F1 generation
Details on results (F1)
No changes were observed between control group and administered groups.
CLINICAL SIGNS (OFFSPRING)
One pup showed anophthalmia and one pup showed polydactyly in 300 mg/kg. However, these incidences were not caused by the test item but natural occurrence.
BODY WEIGHT (OFFSPRING)
Decrease in body weight was observed in males of 100 mg/kg at day 0 after birth, 300 mg/kg at day 0 and 4 after birth, in females at day 4 after birth. However, these changes were regarded as compound related changes since no dose-responsibility was observed.
GROSS PATHOLOGY (OFFSPRING)
Pyelectasis was observed in one dead pup in 100 mg/kg. Red patch of planta was observed in male and female pups 100 mg/kg at day 4 after birth. These pups had the same dam. Therefore, it was not caused by the test item but occurred naturally. Dilated lumen of ureter was observed in male and female pups in administered groups. However, these changes were not caused by the test item but occurred naturally since no dose-responsibility was detected and several litter had the same dam.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- (development)
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects on reproduction parameters
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
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.
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