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REACH

β-bromostyrene

EC number: 203-131-3 | CAS number: 103-64-0

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Repeated dose toxicity: Oral

In a Subacute repeated dose oral toxicity study, Sprague Dawley [Crl:CD()SD] male and female rats treated with the test chemical orally by gavage in the concentration of 0 (corn oil), 30, 125 and 500 mg/kg/day for 28 days. Recovery group animals for a duration of 14 days were also included in the study other than the test group animals. The animals were observed for clinical signs, mortality, changes in body weight, food and water consumption, urinanalysis, hematology, clinical chemistry, neurobehavioral parameters were noted and the animals were sacrificed for gross and histo-pathology

One female rat was found dead on Day 3 and Decreases in spontaneous movement during weeks 3 and 4 were observed in male and female rats. No clinical signs were observed in any animal during the recovery period. Significantly increased body weight was observed in female rat on days 17-24 during the dosing period and significant decrease in water consumption was observed in female rats during week 4 of the dosing period a 125 mg/kg/day dose group as compared to control. Significant decreased in food consumption at day 4 were observed in male and female rat in dosing period and in females at days 7 and 14 in recovery period at 500 mg/kg/day and significant increased in food consumption at days 7-21 were observed in female rats at 125 mg/kg/day as compared to control. Decreased mean corpuscular hemoglobin (MCH) during dosing and eosinophils in recovery period were observed in male rat and increased reticulocyte and decreased mean corpuscular hemoglobin concentration (MCHC) during dosing and increase monocytes at recovery period were observed in female rats and significant increased in total protein level in male and female rats, Ca, P and albumin level and decrease in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and creatinine in male rats and significant increased in total cholesterol, triglycerides, phospholipids and Cl level in female rats at the end of dosing. Significant increased in triglycerides level was observed in female rats after the recovery period at 500 mg/kg/day. Decreased activated partial thromboplastin time and increased fibrinogen level were observed in female rats andsignificant decrease in aspartate aminotransferase, lactate dehydrogenase level and significant increased in Ca level in male rats and significant increased in total cholesterol, phospholipids level in female rats observed at 125 mg/kg/day as compared to control. Significant increases in urine volume in male and female rats, decrease in urine osmolality and small round epithelial cells in sediments were observed in male rats during week 4 of dosing period at 500 mg/kg/day and significant increases in urine volume and significant decrease in urine osmolality were observed in male rats at 125 mg/lg/day as compared to control. No significant differences were seen in urine volume, osmolality and qualitative measurements for either sex compared with the control groups during week 2 of the recovery period. Significant decrease in landing foot splay and forelimb grip strength was observed in male rats during week 2 of the recovery period. However, it was determined to be incidental because this sign was not observed during week 4 of the dosing period at 500 mg/kg/day. Significant decrease in forelimb grip strength was observed in male rats during week 2 of recovery period. No significant change was observed in any male and female rats receiving the test substance during week 4 of the dosing period. Significant increase in hindlimb grip strength was observed in female rats during week 4 of the dosing period at 125 mg/kg/day as compared to control. However, this was not observed in the high dose group. Similarly, Significant increase in absolute and relative liver weight in male and female rats, significant increase in absolute and relative kidney weights and significant decrease in absolute testes weight in male rats and significant increase in relative kidney weights in female rats in dosing period and significant increase in relative liver and heart weight was observed in female rats at 500 mg/kg/day as compared to control at the end of recovery period. Significant increase in relative liver weight and decrease in brain weight were observed at 125 mg/kg/day in female rats at the end of the recovery period. In addition, excess fluids in the abdominal and thoracic cavities, an enlarged liver, and dark red foci in the glandular stomach and unilateral small thyroids observed in female rat and enlargement of liver was observed in male rats at the end of dosing period. Enlargement of liver was observed in male rats at the end of recovery period in 500 mg/lg/day. Dark red foci in lung in one male rat and dark red foci in the glandular stomach in one female rat were observed at end of the dosing period at 125 mg/kg/day dose group. Minimal to mild degree of eosinophilic bodies in tubular cells, Mild degeneration of renal tubular and minimal hyaline casts in kidneys, minimal to mild centrilobular hypertrophy of hepatocytes in liver and minimal hypertrophy of follicular cells in thyroids were observed in male rats and atrophy of Peyer’s patch in the ileum, dilation of the renal tubes with centrilobular necrosis and congestion in the liver, focal hemorrhage and accumulation of foamy cells in the lung, atrophy of the mesenteric and submandibular lymph nodes, an increase in hematopoiesis and atrophy of white pulp in the spleen, erosion in the glandular stomach, atrophy of the thymus, and a remnant of ultimobranchial bodies in the thyroid were observed in female rats at 500 mg/kg/day as compared to control. Minimal Tubular regeneration, mild to minimal Eosinophilic body in tubular cells interstitial mineralization Kidney and Hypertrophy of follicular cells in thyroid of male rat and Periportal vacuolation of hepatocytes in liver of female rat were observed at the recovery period. Minimal to mild degree of eosinophilic bodies in tubular cells in kidney was observed in male rat and minimal hypertrophy of follicular cells in thyroids was observed in female rats at 125 mg/kg/day as compared to control.

Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 30 mg/kg/day when Sprague Dawley [Crl:CD()SD] male and female rats were treated with the test chemical for 28 days.

Repeated dose toxicity: Inhalation

The repeated dose inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 0.123 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study for repeated dose toxicity by inhalation route of exposure is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value forβ- bromostyrene (CAS no 103-64-0)(as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

Subacute repeated dose toxicity study was performed to determine the toxic nature of the test chemical orally in rats

GLP compliance:

not specified

Limit test:

Species:

rat

Strain:

Crj: CD(SD)

Remarks:

Sprague Dawley

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Atsugi Atsugi Breeding Center of Charles River Japan, Inc. (Kanagawa, Japan).
- Age at study initiation: 6 weeks
- Weight at study initiation: 182-216g for males and 145-171 g for females
- Fasting period before study: No data available
- Housing: Animals were individually housed in wire-mesh steel bracket cages (W 250 × D 350 × H 200 mm) and identified by using ear tags.
- Diet (e.g. ad libitum): Pellet diet (CRF -1,oriental yeast co., Tokyo, Japan), ad libitum
- Water (e.g. ad libitum): Tap water through bottle, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 degree C
- Humidity (%): 49-66%
- Air changes (per hr): 10-15 times/hr
- Photoperiod (hrs dark / hrs light): 12 hr/day (light on/off, 7:00/19:00).

IN-LIFE DATES: From: To :No data available

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in corn oil to give a dose range of 0, 30, 125 or 500 mg/kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food):No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 30, 125 and 500 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): Lot no. WKJ3948
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily

Remarks:

0, 30, 125 or 500 mg/kg/day

No. of animals per sex per dose:

Total: 72
0 mg/kg/day: 6 male, 6 female
30 mg/kg/day: 6 male, 6 female
125 mg/kg/day: 6 male, 6 female
500 mg/kg/day: 6 male, 6 female

For recovery period:
0 mg/kg/day: 6 male, 6 female
500 mg/kg/day: 6 male, 6 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose level were selected based on results obtained from 14-days range finding study using the same strains of rats. All males and females in the 1000 mg/kg died. Increases in relative liver and kidney weights were observed in 300 mg/kg group. Therefore, for the present study high dose was set at 500 mg/kg/day and middle and low doses was set at 125 and 30 mg/kg/day.

- Rationale for animal assignment (if not random): Stratified random sampling based on body weight
- Rationale for selecting satellite groups: 6 male and 6 female of 0 and 500 mg/kg/day dose group kept without treatment as a recovery group.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random):No data available

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2-3 times daily during dosing period and once daily during recovery period.
- Cage side observations checked in table [No.?] were included. Morbidity and mortality were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before the start of dosing and once a week during dosing and recovery periods.

BODY WEIGHT: Yes
- Time schedule for examinations: Before dosing and on days 1,4,7,10,14,17,21,24 and 28 for dosing periods and on days 1,3,7,10, and 14 for the recovery period

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption was measured on days 1,4,7,10,14,17,21,24 and 28 for dosing periods and on days 1,3,7,10, and 14 for the recovery period
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations:week 4 for dosing period and week 2 of recovery period

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At day after end of dosing and recovery period
- Anaesthetic used for blood collection: Yes ,blood was collected from abdominal aorta under deep anesthesia
- Animals fasted: Yes, overnight fasting was performed
- How many animals: From all 72 animals
- Parameters checked in table [No.?] were examined.: red blood cell (RBC), Hemoglobin, hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin,platelets, prothrombin volume, WBC , lymphocytes, neutrophils, eosinophils,basophils,monocytes, large unstained cells and blood clotting parameters, such as prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen level (FIB) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of dosing period and at the end of recovery period
- Animals fasted: Yes, overnight fasting was performed
- How many animals: From all 72 animals
- Parameters checked in table [No.?] were examined.: Serum was analyzed for alkaline phosphatase (ALP), total cholesterol (T-CHO), triglyceride (TG), phospholipid (PL), total bilirubin (T-BIL), glucose (GLU), blood urea nitrogen (BUN), creatinine (CRNN), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), inorganic phosphorus (P), total protein (TP), albumin (ALB), and albumin/globulin (A/G) ratio. Plasma isolated from heparinized blood was analyzed for aspartate and alanine aminotransferases (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and γ-glutamyl transpeptidase (γ-GTP). Electrolytes were also analyzed

URINALYSIS: Yes
- Time schedule for collection of urine: Urinalysis was conducted during Week 4 in the dosing period and Week 2 in the recovery period
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes, 4 hrs fasting was performed with water ad libitum
- Parameters checked in table [No.?] were examined.: dipstick parameters, such as pH, proteins, ketone bodies, glucose, occult blood, bilirubin, urobilinogen, color, sediments, and volume. Urine volume and osmolality were also measured

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: At the end of the dosing and recovery periods
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: functional observation including auditory, approach, touch, and tail pinch response, pupilary and aerial righting reflexes.in addition grip strengths were measured using CPU guage and motor activity was recorded at 10 min. interval for 1 hour.

OTHER:After blood collection

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all animals were sacrificed by exsanguination, and the organs and tissues of the whole body, including external surfaces, head, breast, and abdomen were observed macroscopically. The brain, adrenals, thymus, spleen, heart, liver, kidneys, testes, epididymides, ovaries, and uterus were removed and
weighed. In addition, relative organ weights were calculated from organ/body weight ratios.

HISTOPATHOLOGY: Yes, The cerebrum, cerebellum, spinal cord (chest), sciatic nerve, pituitary gland, thyroid, parathyroids, adrenal glands, thymus, spleen, submandibular lymph nodes, mesenteric lymph nodes, heart, trachea, lung (including bronchial), stomach, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectum, liver, kidneys, urinary bladder, testes, epididymides, prostate, ovaries, uterus, sternum (including bone marrow), femur (including bone marrow), and femoral skeletal muscle were fixed in 10% phosphate-buffered formalin. The eyeballs and optic nerves were fixed in phosphate-buffered 3 vol% glutaraldehyde/2.5 vol% formalin, and the testes and epididymides were fixed in Bouin’s solution.

Paraffin sections for microscopic examination were routinely prepared and stained with hematoxylin-eosin. In the control and high dose groups sacrificed at the end of the dosing period, all preserved organs were examined under a light microscope. If treatment-related histopathological changes were found, the same tissues were examined for low and middle dose groups and the recovery group.

Statistics:

Statistical analysis were performed by using Bartlett’s test for homogeneity of distribution for quantitative data in open field observation, functional observation and urinalysis, grip strengths, motor activity, body weight, food and water consumption, hematological and blood biochemistry findings, and organ weights. The Dunnett’s multiple comparison test and the Dunnett’s-type mean rank sum test were conducted for homogenous and non-homogenous distribution, respectively to compare the control and individual treatment groups. Parametric data obtained during or after the recovery period were analyzed by F-test for homogeneity of distribution. For comparison, the Student’s t-test and the Aspin-Welch’s t-test were conducted for homogenous and non-homogenous distribution.

Clinical signs: