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EC number: 603-094-7 | CAS number: 125904-11-2
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 April to 12 May 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- The highest dose level exceeded the limit dose (i.e. 1600 mg/kg bw/day instead of 1000 mg/kg bw/day)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA TSCA, 40 CFR Part 798.4900, May 20, 1987
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Benzene, dibromoethyl Benzene, ethenyl-, ar-bromo derivs.
- EC Number:
- 603-094-7
- Cas Number:
- 125904-11-2
- Molecular formula:
- C8 H6 Br2
- IUPAC Name:
- Benzene, dibromoethyl Benzene, ethenyl-, ar-bromo derivs.
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: approx. 14 weeks
- Weight at study initiation: 222 to 315 g
- Housing: individually in wire-mesh cages suspended above cage-board
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002 ad libitum
- Water (e.g. ad libitum): tap water delivered by an automatic watering system ad libitum
- Acclimation period: 33 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68 to 75 °F
- Humidity (%): 32 to 95%
These values were outside the terget ranges in a few occasions. These deviations had no impact on the outcome of the study.
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: From: day 6 of pregnancy To: day 17 of pregnancy
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Remarks:
- Mazola
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The appropriate amounts of dibromostyrene were weighed for each group and transferred to graduated cylinders via a series of vehicle rinses. Specified amounts of vehicle were then added. The preparations were inverted and shaken several times and then transferred to individual storage containers. An additional amount of vehicle was added to the storage container via a series of rinses to achieve the appropriate concentration for each group. The prepartions were stirred for at least 10 minutes using a magnetic plate and stir bars. From the storage container, a sufficient number of bottles were filled for each group. The bottles were stored frozen. The dosing suspensions were prepared weekly. One bottle per group was thawed at room temperature and mechanically stirred each day before and during administration to the animals. All test suspensions were used within one hour of thawing. Unused portions of the thawed test suspension were discarded following the completion of dosing each day.
VEHICLE: Mazola corn oil
- Concentration in vehicle: 20, 80, 160 and 320 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were collected from the low and high dose levels prior to study intiation. These pre-samples were analysed for homogeneity and stability. Samples (approximately 10 mL) were collected weekly from each dose level following test material preparation. These samples were analysed for concentration. Samples were analysed using a gas chromatography/flame ionization detection method.
The dosing preparation were homogeneous,contained the designated amount of dibromostyrene and were stable for two weeks when stored frozen. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- From day 6 to 15 of (presumed) pregnancy
- Frequency of treatment:
- Daily
- Duration of test:
- Dams were sacrificed on day 20 of pregnancy
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
400 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
800 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1600 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 25 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dosages were chosen on the basis of a RF study conducted at 100, 200, 400, 800 and 1600 mg/kg bw/day. A maternal response was expressed at dose levels of 800 and 1600 mg/kg bw/day (increased incidence of clinical signs and inhibition of body weight gain and food consumption). Maternal survivial was not affected. A developmental effect was equivocal at 1600 mg/kg bw/day as indicated by slightly reduced foetal body weight.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality, moribundity, general appearance and behaviour; approximately one hour after dosing for clinical signs
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily from day 0 to 20 of gestation (before dosing during the treatment period)
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 3, 6 through 16 and 20 of pregnancy
FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: a complete necropsy was performed, and all abnormalities were recorded. The liver of each dam was excised, trimmed, weighed and the findings recorded. Maternal tissues were retained only as deemed necessary by gross findings.
The uterus and ovaries were excised, the number of corpora lutea on each ovary was recorded; the trimmed uterus was weighed, opened and the number and location of all foetuses, early and late resorptions and the total number of implantation sites were recorded. Uteri with no macroscopic evidence of nidation were excised, opened and subsequently placed in 10% ammonium sulfite solution for detection of early implantation loss accoding to Salewsky. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
OTHER: crown-rump measurements were recorded for late resorptions and the tissues were discarded - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: approx. half per litter - Statistics:
- All analyses were conducted using two-tailed tests (except as noted) for a minimum significance lavel of 5% when comparing each treated group to the vehicle control group. Animals that were not gravid were not included in the claculations of group means for body weights, food consumption and other applicable parameters. The following statistical tests were performed by a digital computer (with appropriate programming):
STATISTICAL TEST PARAMETER
Chi-square test with Yates' correction factor Foetal sex ratio
Fisher's Exact test Malformations and variations
Mann-Whitney U-test Early and late resorptions, dead foetuses, postimplantation losses
One-way ANOVA with Dunnett's test Corpora lutea, total implantations, viable foetuses, foetal bw, maternal bw and bw changes,
maternal net bw chenges and gravid uterine weights, maternal food consumption and maternal
liver weight
Kruskal-Wallis test (one-tailed test) Litter proportion of intrauterine data (considering the LITTER as the experimental unit) - Historical control data:
- Historical control data were included in the report. Relevent reference values were included within the text for discussion of specific findings.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: including the lower dose level
Details on maternal toxic effects:
100 mg/kg bw/day: limited to a decreased body weight gain (not statistically significant) during the first 3 days of treatment and dose-related reduction of food consumption
400 mg/kg bw/day: clinical signs (soft stool, hair loss and yellow or brown matting on several body surfaces); decreased body weight gain during the first 6 days of treatment, accompanied by reduced food consumption
800 mg/kg bw/day: clinical signs (soft stools, decreaed defecation, yellow faeces, bright yellow urine, hair loss and yellow or brown matting on several body surfaces; decreased body weight gain during the first 6 days of treatment, accompanied by reduced food consumption
1600 mg/kg bw/day: marked. Mortalities (5 of 25 animals + one animal sacrificed moribund), clinical signs (lethargy, high carriage, impaired equilibrium, soft stools, mucoid faeces, diarrhea, decreased defecation and urination, orange or yellow faeces, bright yellow or red urine, hair loss on several body surfaces, tan, brown and yellow matting on several body surfaces, red material around the nose, mouth and eyes, and tan staining around the nose and mouth); decreased body weight gain throughout the treatment period; decreased food consumption during the first 6 days of dosing.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- not specified
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
400 mg/kg bw/day: increased incidence of a skeletal specific variation (7th cervical rib)
800 mg/kg bw/day: increased incidence of skeletal variations (sternebrae #5 and/or #6 unossified and 7th cervical rib). These variations were within HC ranges but likely dose related because similar to those observed at the highest dose level. 1 foetus with hydrocephaly was also noted (within HC range)
1600 mg/kg bw/day: decreased mean foetal body weight and increased post-implantation loss (with corresponding decrease in the number of mean viable foetuses). Statistically significant increased number of litters with external malformations, mainly cranio-facial defects (i.e. microphthalmia and/or anopthalmia, total of 37 foetuses from 9 litters, exceeding HC values; mandibular agnathia and aglossia in 3 foetuses, one of which had also microstomia and malpositioned pinnae, from 3 litters, exceeding HC values, cleft palate in one foetus exceeding HC value on a litter basis). Soft tissue malformations were also observed (single foetuses with folded retina and common truncus arteriosus, and two foetuses from the same litter with hydrocephaly - all exceeding HC values). Increased incidence of skeletal variations (sternebrae #5 and/or #6 unossified and 7th cervical rib).
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- skeletal malformations
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Treatment of pregnant rats with dibromostyrene during the organogensis period at dosages of 100, 400, 800 and 1600 mg/kg bw/day caused both maternal and developmental toxic effcts. Maternal toxicity was slight at the lowest dose level of 100 mg/kg bw/day however, based on the slight decreased body weight gain during the first 3 days of dosing and a dose-related decrease in food consumption during the first 6 days of dosing, this dose level was consedered to be a LOAEL. Maternal toxicity increased with increasing dosages as evidenced by the number of clinical signs and effects on body weight gains and food consumption. Maternal toxicity was marked at the highest dose level of 1600 mg/kg bw/day, where 5 dams died and another one was sacrificed muribund. Related to the degree of maternal toxicity, effects on foetuses consisted mainly in increases of of specific skeletal variations at 400 mg/kg bw/day and above, and teratogenic effects, primarily cranio-facial defects, at the highest dose level of 1600 mg/kg bw/day. The NOAEL for developmental toxicity was 100 mg/kg bw/day.
- Executive summary:
In a teratogenicity study in rats, groups of 25 presumed pregnant female rats were traeted daily, from day 6 to 15 of gestation, at dosages of 100, 400, 800 or 1600 mg/kg bw/day. A concurrent vehicle control group received corn oil alone, at a volume of 5 mL/kg bw.
Maternal toxicity was noted at all dose level, expressed by reduced body weight gains and reduced food consumption primarily during the first 3 -6 days of treatment. Clinical signs, increasing in severity and number of occurences, were noted in animals dosed at 400 mg/kg bw/day and above. The highest dose level of 1600 mg/kg bw/day was severely toxic to the dams, causing the death of 5 of them and and the sacrifice moribund of another one. Similarly, developmental toxicity was marked at 1600 mg/kg bw/day, by a decrease in mean foetal weights and an increase in post-implantation loss. in addition, deveopmental toxicity was also noted at dosages of 400 mg/kg bw/day and higher, expressed by external malformations (1600 mg/kg bw/day dose level) and specific skeletal variations (400 mg/kg bw/day and higher). Although body weight gain of females dosed at 100 mg/kg bw/day was only slightly reduced during the first 3 days of dosing, and food consumption was reduced during the first 6 days of dosing, this dose level was set as the LOAEL for maternal toxicity. 100 mg/kg bw/day was NOAEL for deveopmental toxicity.
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