1,4-divinylbenzene

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

The No observed adverse effect level (NOAEL) for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 1000 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Repeated dose toxicity: Inhalation

NOAEC for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 3000 mg/m3.

Repeated dose toxicity: Dermal

In accordance with coloumn 2 of Annex IX, this end point was considered for waiver since the acute toxicity by the dermal route has already been provided in section 7.2.3 (as part of the Annex VIII information requirements)

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:

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:

data from handbook or collection of data

Remarks:

experimental data of read across substances

Justification for type of information:

Data for the target chemical is summarized based on the structurally similar read across chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

WoE derived based on the experimental data from structurally and functionally similar read across chemicals

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: 1. Sprague-Dawley-derived (Crl:CD@ BR); 2. F344

Sex:

male/female

Details on test animals or test system and environmental conditions:

1. TEST ANIMALS- Source: Charles River Laboratories, Inc. (Raleigh, NC)- Age at study initiation: 46 days- Weight at study initiation: 227.3-276.1 g males, 153.2-195.8 g females- Fasting period before study: No data- Housing: The rats were housed in stainless-steel wire-bottomed suspended cages, color-coded for dosage level. The rats within any treatment level were caged vertically to minimize light, temperature, and airflow differences between exposure groups- Diet (e.g. ad libitum): Purina Rodent Chow No. 5002 (Ralston Purina Co., St. Louis, MO) ad libitum- Water (e.g. ad libitum): Tap water ad libitum- Acclimation period: 2 weeksENVIRONMENTAL CONDITIONS- Temperature (°C): 22-24°C- Humidity (%):40-60%- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): 12-h light-dark cycleIN-LIFE DATES: From: To: No data2. TEST ANIMALS- Source: Harlan Industries Inc. (Cumberland. IN)- Age at study initiation: No data- Weight at study initiation: No data- Fasting period before study:- Housing: Animals were housed five per cage in polycarbonate cages. The bedding material used was Absorb-Dri. The cage filters used were Reemay spun-bonded polyester filters.- Diet (e.g. ad libitum): Purina Lab Chow (Ralston Purina, studiesSt. Louis, MO); available ad libitum- Water (e.g. ad libitum): No data- Acclimation period: 14 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 21°-23° C- Humidity (%): 40%-60%- Air changes (per hr): 15 room air changes/h- Photoperiod (hrs dark / hrs light): fluorescent light 12 h/dIN-LIFE DATES: From: To: No data

Route of administration:

other: 1. Unspecified; 2. Gavage

Vehicle:

other: Corn oil

Details on oral exposure:

1. PREPARATION OF DOSING SOLUTIONS: The chemical was dissolved in corn oil at dose levels of 0, 200, 600 or 1800 mg/Kg/dayDIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): Corn oil- Concentration in vehicle: 0, 200, 600 or 1800 mg/Kg/day- Amount of vehicle (if gavage): No data- Lot/batch no. (if required): No data- Purity: No data2. PREPARATION OF DOSING SOLUTIONS: Weighed portion of1,4-dichlorobenzene and corn oil mechanically stirred in volumetric flask for 1 h; lower doses prepared by serial dilution.DIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): Corn oil- Concentration in vehicle: 0, 60, 125, 250,500, or 1,000 mg/kg- Amount of vehicle (if gavage): 5 mL/Kg- Lot/batch no. (if required): No data- Purity: No data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

1. The purity was determined to be greater than 98% by gas chromatographic-mass spectral analysis (GC-MS)2. Dose mixtures were analyzed at approximately 8-week intervals during the 2 year studies. All of the samples analyzed were within ± 10% of the target concentrations

Duration of treatment / exposure:

14 days

Frequency of treatment:

1. 7 days/week2. Daily

Remarks:

1. Doses / Concentrations:0, 200, 600 or 1800 mg/Kg/day

Remarks:

2. 1. Doses / Concentrations:0, 60, 125, 250,500, or 1,000 mg/kg

No. of animals per sex per dose:

1. Total: 800 mg/Kg/day: 10 males and 10 females200 mg/Kg/day: 10 males and 10 females600 mg/Kg/day: 10 males and 10 females1800 mg/Kg/day: 10 males and 10 females2. Total: 30 males and 30 females0 mg/Kg: 5 males and 5 females60 mg/Kg: 5 males and 5 females125 mg/Kg: 5 males and 5 females250 mg/Kg: 5 males and 5 females500 mg/Kg: 5 males and 5 females1000 mg/Kg: 5 males and 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

1. - Dose selection rationale: The high-dose level was chosen as one half of the reported LD50 and was expected to produce a toxic effect. The lowest dose was selected to be a no-effect level.- Rationale for animal assignment (if not random): Yes, randomized- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data2. - Dose selection rationale: No data- Rationale for animal assignment (if not random): Assigned to cages by table of random numbers, then to groups byanother table- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data

Positive control:

No data

Observations and examinations performed and frequency:

1. CAGE SIDE OBSERVATIONS: Yes- Time schedule: Twice daily for Mortality, Morbidity. All rats were observed daily by careful cageside observation. Physicalexaminations were performed weekly- Cage side observations checked in table [No.?] were included. Mortality, Morbidity, overt signs of toxicity, DETAILED CLINICAL OBSERVATIONS: Yes, any abnormalities in housing. food, water, or clinical signs involving general appearance, behavior, excretion, respiration, skin, pelage. or eyes were recorded- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: Individual body weights were measured prior to randomization, at initiation of dosing, and weekly thereafteFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Food consumption was measured weekly- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: Yes- Time schedule for collection of blood: Prior to necropsy- Anaesthetic used for blood collection: Yes, ketamine- Animals fasted: Yes, overnight fasting- How many animals: All animals- Parameters checked in table [No.?] were examined. leukocyte, erythrocyte. hematocrit, and hemoglobin tests; leukocyte differentials and cell morphologyCLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: Prior to necropsy- Animals fasted: Yes, overnight fasting- How many animals: All animals- Parameters checked in table [No.?] were examined. sodium, potassium, total protein, albumin, calcium, total bilirubin, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH). and blood urea nitrogenURINALYSIS: Yes- Time schedule for collection of urine: Prior to necropsy- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.?] were examined. pH, glucose, protein, bilirubin, occult blood. and urobilinogenNEUROBEHAVIOURAL EXAMINATION: Y No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER: No data2. CAGE SIDE OBSERVATIONS: Yes- Time schedule: Twice Daily- Cage side observations checked in table [No.?] were included. Mortality and general observations DETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: No dataFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: No data- Time schedule for collection of blood: No data- Anaesthetic used for blood collection: No data - Animals fasted: No data- How many animals: No data- Parameters checked in table [No.?] were examined. No dataCLINICAL CHEMISTRY: No data- Time schedule for collection of blood: No data- Animals fasted: No data- How many animals: No data- Parameters checked in table [No.?] were examined. No dataURINALYSIS: No data- Time schedule for collection of urine: No data- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.?] were examined. No dataNEUROBEHAVIOURAL EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER:

Sacrifice and pathology:

1. GROSS PATHOLOGY: Yes, Animals were weighed. anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys. spleen, adrenal glands. thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated.Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal.HISTOPATHOLOGY: Yes, The following tissues were evaluated from all animals in the 600 mgikg per day animals in the 14-day study as well as from five randomly selected animals per gender in corn oil control animals: adrenals, thyroid, esophagus, trachea, larynx, heart, spleen, liver, kidney, stomach, duodenum, jejunum, colon, pancreas, and gross lesions.2. GROSS PATHOLOGY: Yes, necropsy was performed on all animalsHISTOPATHOLOGY: Yes, selected animals received histologic exam

Other examinations:

No data

Statistics:

1. All appropriate data were subjected to Levene's test of homogeneity of variance and an analysis of variance. Non-homogeneous data were subjected to a series of transformations in order to achieve homogeneity . When the series of transformations were ineffective in achieving homogeneity, analysis of ranked data were performed. Group comparisons were evaluated using Dunnett's t-test at the 5.0% two-tailed probability Ievel.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1. Animals at 1800 mg/Kg bw frequently exhibited prostration, salivation, and tremors following dosing2. One male rat had a punctured esophagus, indicating probable gavage error.

Mortality:

mortality observed, treatment-related

Description (incidence):

1. At 1800 mg/Kg bw- Males- 8/10 Females- 8/10 2. One male rat in the 125 mg/kg group died before the end of the studies

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1. A statistically significant decrease in body weight was exhibited by both males and females in the high-dose group (1800 mg/kg/day) at Weeks 1 and 2. Body weight gain (Weeks 0-2) for these animals was also significantly decreased. Mid-dose males (600 mg/kp/day) exhibited a significant decrease in body weight gain (Weeks 0-2).2. The final mean body weights of dosed male rats were 7%-12% lower than that of the controls; however, there was no clear dose related trend. The final mean body weights of the female rats were not affected in a dose related manner.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1. Total food consumption (Week 1) was significantly decreased for males in the mid- and high-dose groups.2. No data

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

No treatment related effects were noted

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:

effects observed, treatment-related

Description (incidence and severity):

1. Organ weight comparisons between mid-dose animals with control animals revealed a number of differences: all were considered related to a lower terminal body weight or considered to be a general indication of stress.2. No data

Gross pathological findings:

no effects observed

Description (incidence and severity):

1. No treatment related gross pathology effects were noted2. No compound-related effects were observed at necropsy

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

2. No compound-related effects were observed after microscopic examination in either sex.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

2. No compound-related effects were observed after microscopic examination in either sex.

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Remarks:

1

Effect level:

600 other: mg/Kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment related effects were noted

Dose descriptor:

NOAEL

Remarks:

2

Effect level:

1 000 other: mg/Kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Critical effects observed:

not specified

Conclusions:

The No observed adverse effect level (NOAEL) for the test chemical 1-bromo-4-fluorobenzene (CAS no 460 -00 -4) is considered to be 1000 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of 1,4-divinylbenzene (CAS no 105-06-6). The studies are as mentioned below:

Study 1:

14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. Male and female Sprague Dawley rats were dosed daily at dose levels of 0, 200, 600 or 1800 mg/Kg/day for 14 days. The animals were observed for cage side observations, clinical signs, body weight and food consumtion, hematology, clinical pathology parameters and usinalysis following gross and histopathology. Treatment related severe effects were noted at 1800 mg/Kg/day. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 600 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Study 2:

In another study, 14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compound. The study was performed using male and female F344 rats. The test chemical was dissolved in corn oil and used at dose level of 0,60, 125, 250, 500, or 1,000 mg/kg for 14 days. During the study, the test animals were observed for clinical signs, mortality, body weight changes and were subjected to gross and histopathology.One male rat in the 125 mg/kg group died before the end of the study. One male rat had a punctured esophagus, indicating probable gavage error. The final mean body weights of dosed male rats were 7%-12% lower than that of the controls; however, there was no clear dose related trend. The final mean body weights of the female rats were not affected in a dose related manner. No compound-related effects were observed at necropsy or after microscopic examination in either sex. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg for F344 rats when exposed for 14 days.

Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 1000 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from peer reviewed publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Type of 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:

data from handbook or collection of data

Remarks:

experimental data of read across substances

Justification for type of information:

Data for the target chemical is summarized based on the structurally similar read across chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

WoE derived based on the experimental data from structurally and functionally similar read across chemicals

GLP compliance:

not specified

Limit test:

no

Species:

other: 1. rats; 2. mouse

Strain:

other:

Remarks:

Alderley Park

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animalTEST ANIMALS- Source: SPF- Age at study initiation:- Weight at study initiation: No data- Fasting period before study: Overnight- Housing: The animals were housed 9-10/cage- Diet (e.g. ad libitum): No data- Water (e.g. ad libitum): No data- Acclimation period: No dataENVIRONMENTAL CONDITIONS- Temperature (°C): No data- Humidity (%): No data- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: From: To: No data

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: 2m3 stainless steel chamber- Method of holding animals in test chamber: No data- Source and rate of air: No data- Method of conditioning air: No data- System of generating particulates/aerosols: The test chemical vapour atmospheres were generated by passing clean dry air through the test chemical (99.8".) ill a water-jacketed vessel, which was thermostatically controlled at 55 C- Temperature, humidity, pressure in air chamber: No data- Air flow rate: The required exposure levels were obtained by adjusting the air flow through the test chemical crystals into the exposure chamber- Air change rate: No data- Method of particle size determination: No data- Treatment of exhaust air: No dataTEST ATMOSPHERE- Brief description of analytical method used: No data- Samples taken from breathing zone: No dataVEHICLE (if applicable)- Justification for use and choice of vehicle: Air- Composition of vehicle:- Type and concentration of dispersant aid (if powder): No data - Concentration of test material in vehicle: 0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3)- Lot/batch no. of vehicle (if required): No data- Purity of vehicle: No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

1. 76 weeks2. 57 weeks

Frequency of treatment:

Daily

Remarks:

0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3)

No. of animals per sex per dose:

1. 76-79 rats of both sexes2. 75 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

1. CAGE SIDE OBSERVATIONS: Yes- Time schedule: at regular intervals- Cage side observations checked in table [No.?] were included. Clinical condition DETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: Yes - Time schedule for examinations: at regular intervalsFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, at regular intervals- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes- Time schedule for examinations: at regular intervalsOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: Yes- Time schedule for collection of blood: wk 5, 14, 26-27, 40 and 52-53.- Anaesthetic used for blood collection: Yes (identity) / No / No data- Animals fasted: Yes / No / No data- How many animals:- Parameters checked in table [No.?] were examined. Standard parametrsCLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: wk 5, 14. 27, 40 and52.- Animals fasted: No data- How many animals: 5/sex- Parameters checked in table [No.?] were examined. blood urea, blood glucose and plasma alanine and aspartate-transaminase activities. Hepatic aminopyrine-demethylase activity was determined at wk 52 53 on five animals of each sexand groupURINALYSIS: Yes- Time schedule for collection of urine: wk 5, 14. 27, 40 and52.- Metabolism cages used for collection of urine: No data- Animals fasted: No data - Parameters checked in table [No.?] were examined. Urine analyses and urinarycopoporphyrin excretionNEUROBEHAVIOURAL EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER: No data2. CAGE SIDE OBSERVATIONS: Yes- Time schedule: at regular intervals- Cage side observations checked in table [No.?] were included. Clinical condition DETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: No data- Time schedule for examinations: No dataFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, at regular intervals- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes- Time schedule for examinations: at regular intervalsOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: No data- Time schedule for collection of blood: No data- Anaesthetic used for blood collection: No data- Animals fasted: No data- How many animals: No data- Parameters checked in table [No.?] were examined. No dataCLINICAL CHEMISTRY: No data- Time schedule for collection of blood: No data - Animals fasted: No data- How many animals: No data- Parameters checked in table [No.?] were examined. No dataURINALYSIS: No data- Time schedule for collection of urine: No data - Metabolism cages used for collection of urine: No data- Animals fasted: No data - Parameters checked in table [No.?] were examined. No data NEUROBEHAVIOURAL EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER: No data

Sacrifice and pathology:

1. Sacrifice and pathologyGROSS PATHOLOGY: Yes, Rats found dead, killed in extremis or scheduled for interim or terminal kills were subjected to detailed gross examination. Some organ weights were recorded.HISTOPATHOLOGY: Yes, Rats Found dead, killed in extremis or scheduled for interim or terminal kills were subjected to detailed histopathologic examination. Adrenals, aorta, urinary, bladder, caecum, colon, cervix, duodenum, epididymis, heart, ileum, lymph nodes, (cervical, thoracic and mesenteric), jejenum, kidneys, liver, lungs, mammary gland, oesophagus, ovaries, pancreas, prostate, salivary glands, seminal vesicle, spleen, stomach, testes, larynx, trachea, thymus, thyroid, uterus, voluntary muscle, zymbal's gland. Harderian gland, bone (marrow), brain, sciatic nerve, nasal sinuses, pituitary, eye and spinal cord were examined.2. GROSS PATHOLOGY: Yes, mice found dead, killed in extremis or scheduled for interim or terminal kills were subjected to detailed gross examination. Some organ weights were recorded.HISTOPATHOLOGY: Yes, histopathology on tile following tissues was performed on female mice that had received theirtreatment for tit least 52 wk: adrenals, aorta, urinary bladder, caecum, colon, cervix, duodenum, heart, ileum, lymph nodes (cervical, thoracic and mesenteric), harderian shred, jejunum, kidneys, liver, lungs, mammary gland, oesophagus, ovaries, pancreas, salivary glands, spleen, stomach, trachea, thymus, thyroid, uterus, voluntary muscle, Zymbal's gland, bone (marrow), brain, sciatic nerve, nasal sinuses, pituitary, eye and spinal cord.

Statistics:

No data

Clinical signs:

no effects observed

Description (incidence and severity):

No overt signs of exposure-related effect were reported

Mortality:

no mortality observed

Description (incidence):

1. The mortality of the exposed rats was similar to that of the control animals throughout the study2. The mortality in the female mice did not appear to be related to the exposure. The percentage mortality for the 0-, 75- and 500-ppm exposure levels being 17, 19 and 13, respectively, at wk 52, 40, 32 and 35, respectively, at wk 72.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

1. No treatment-related changes in body weight

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

1. No treatment-related changes in food intake

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

1. No treatment-related changes in water intake

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

1. Some changes in hematology parameters were observed but found to be independent of treatment

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

1. Some changes in blood biochemistry were observed but found to be independent of treatment. There was also no indication of an increased activity of hepatic aminopyrine demethylase.

Urinalysis findings:

no effects observed

Description (incidence and severity):

1. Urinary protein and coproporphyrin output was slightly elevated in tile 500-ppm group. This might have been related to functional changes in the liver or kidney, although there was no histological evidence for an effect in these organs

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Description (incidence and severity):

1. Liver and kidney weights were increased, giving further evidence of an effect at 500 ppm. Small increases in the weights of heart and lung tit 500 ppm were not related to any histological change and probably did not represent evidence of any effect of treatment. Bile changes in liver and kidney weights probably indicatedmilder manifestations of those changes seen at higher exposure levels. Apart from some suggestions of increased liver weight, no changes from control values could be discerned at the 75-ppm level and this dose was considered to be without toxicological effect

Gross pathological findings:

no effects observed

Description (incidence and severity):

1. The rats, except the controls which appeared to be normal, exhibited hemorrhagic areas in the lungs of varying degrees as well as a very bright reddish color to either one or both lungs. The heart was of normal size and color in all animals. The majority showed no liver abnormality with the exception of a few which exhibited white streaks on the surface. The kidneys appeared to be normal except for a few that were swollen.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

1. The animals showed little variation of histological change. Hyperemic and edematous areas were most frequently encountered in the lungs. The epithelium of the bronchi did not appear to be much changed in most cases. Occasionally a dissociation of the epithelium of the bronchi was seen but never very clearly. Fresh hemorrhages in the lungs were observed, mainly in the bronchi. No hypertrophy of the lymphoid tissue was noted. A pyknotic appearance of the nuclei was common. Neither damage to the cells nor hepatitis was observed in the liver sections of the rats. Some hyperemic and edematous areas were seen. All the rats showed extensive damage to the kidneys. The epithelium of the tubules was swollen in most cases. The glomeruli were swollen and hyperemic with very marked pyknosis. Almost all the tubules showed varying degrees of necrobiosis. Some animals showed degeneration and loss of alignment of the nuclei. A few of the animals showed a granular exudate in the collecting tubules. Generally the damage to the kidneys was severe. No definite heart damage was observed. Occasionally an edematous area was noted but the nuclei and striation were intact and visible. 2. Histopathological evaluation of the tissues of the female mice revealed a number of age-related changes. A high background incidence of respiratory disease was seen in all groups. This made the interpretation of the findings of the respiratory tract difficult to assess. However, there was no evidence of any treatment-related non-neoplastic effects in these or other tissues examined.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

1. No treatment-related effect on the incidence of tumours, their multiplicity or malignancy was seen in either tile males or females exposed to test chemical vapour at levels up to 500 ppm.2. The neoplastic lesions were of low incidence in this study. The only tumours seen in the respiratory tract were lung adenomas, which were seen at similar rates of incidence in test and control animals, and one osteosarcoma in the nasal sinus of one animal at the 75-ppm level. The incidence, localization and malignancy of these and the other types of tumours did not indicate any carcinogenic activity of the test chemical at levels up to 500 ppm in the female mice.

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEC

Effect level:

3 000 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Critical effects observed:

not specified

Conclusions:

The No observed adverse effect level (NOAEL) for the test chemical 1-bromo-4-fluorobenzene (CAS no 460-00-4) is considered to be 3000 mg/m3.

Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of 1,4-divinylbenzene (CAS no 105-06-6). The studies are as mentioned below:

Study 1:

Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and female Alderley Park Wistar-derived strain rats. The test chemical was generated in vapor form and exposed to animals at dose levels of0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3) for5 hr/day on 5 days/wk in stainless steel containers. During the study, the animals were observed for clinical signs, mortality, changes in body weight, food intake, water intake, hematology, clinical chemistry, urinalysis and subjected to gross and histopathology. No overt signs of exposure-related effect were reported and the mortality of the exposed rats was similar to that of the control animals throughout the study. No treatment-related changes in body weight, food and water intake. Some changes in hematology and blood chemistry parameters were observed but found to be independent of treatment. There was also no indication of an increased activity of hepatic aminopyrine demethylase. Urinary protein and coproporphyrin output was slightly elevated in tile 500-ppm group. This might have been related to functional changes in the liver or kidney, although there was no histological evidence for an effect in these organs. Liver and kidney weights were increased, giving further evidence of an effect at 500 ppm. Small increases in the weights of heart and lung tit 500 ppm were not related to any histological change and probably did not represent evidence of any effect of treatment. Bile changes in liver and kidney weights probably indicated milder manifestations of those changes seen at higher exposure levels. Apart from some suggestions of increased liver weight, no changes from control values could be discerned at the 75 -ppm level and this dose was considered to be without toxicological effect. The rats, except the controls which appeared to be normal, exhibited hemorrhagic areas in the lungs of varying degrees as well as a very bright reddish color to either one or both lungs. The heart was of normal size and color in all animals. The majority showed no liver abnormality with the exception of a few which exhibited white streaks on the surface. The kidneys appeared to be normal except for a few that were swollen. The animals showed little variation of histological change. Hyperemic and edematous areas were most frequently encountered in the lungs. The epithelium of the bronchi did not appear to be much changed in most cases. Occasionally a dissociation of the epithelium of the bronchi was seen but never very clearly. Fresh hemorrhages in the lungs were observed, mainly in the bronchi. No hypertrophy of the lymphoid tissue was noted. A pyknotic appearance of the nuclei was common. Neither damage to the cells nor hepatitis was observed in the liver sections of the rats. Some hyperemic and edematous areas were seen. All the rats showed extensive damage to the kidneys. The epithelium of the tubules was swollen in most cases. The glomeruli were swollen and hyperemic with very marked pyknosis. Almost all the tubules showed varying degrees of necrobiosis. Some animals showed degeneration and loss of alignment of the nuclei. A few of the animals showed a granular exudate in the collecting tubules. Generally the damage to the kidneys was severe. No definite heart damage was observed. Occasionally an edematous area was noted but the nuclei and striation were intact and visible. No treatment-related effect on the incidence of tumours, their multiplicity or malignancy was seen in either tile males or females exposed to test chemical vapour at levels up to 500 ppm. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 3000 mg/m3.

Study 2:

In the same study, combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using female Alderley Park derived strain mice. The test chemical was generated in vapor form and exposed to animals at dose levels of0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3). During the study, the animals were observed for clinical signs, mortality and subjected to gross and histopathology. No overt signs of exposure-related effect were reported and the mortality of the exposed mice was similar to that of the control animals throughout the study. The mortality in the female mice did not appear to be related to the exposure. The percentage mortality for the 0-, 75- and 500-ppm exposure levels being 17, 19 and 13, respectively, at wk 52, 40, 32 and 35, respectively, at wk 72. Histopathological evaluation of the tissues of the female mice revealed a number of age-related changes. A high background incidence of respiratory disease was seen in all groups. This made the interpretation of the findings of the respiratory tract difficult to assess. However, there was no evidence of any treatment-related non-neoplastic effects in these or other tissues examined. The neoplastic lesions were of low incidence in this study. The only tumours seen in the respiratory tract were lung adenomas, which were seen at similar rates of incidence in test and control animals, and one osteosarcoma in the nasal sinus of one animal at the 75-ppm level. The incidence, localization and malignancy of these and the other types of tumours did not indicate any carcinogenic activity of p-DCB at levels up to 500 ppm in the female mice.

Based on the observations made, the NOAEC for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 3000 mg/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

3 000 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from peer reviewed publication

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal, other

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral

Data available for the test chemicals was reviewed to determine the toxic nature of 1,4-divinylbenzene (CAS no 105-06-6). The studies are as mentioned below:

Study 1:

14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test chemical. Male and female Sprague Dawley rats were dosed daily at dose levels of 0, 200, 600 or 1800 mg/Kg/day for 14 days. The animals were observed for cage side observations, clinical signs, body weight and food consumtion, hematology, clinical pathology parameters and usinalysis following gross and histopathology. Treatment related severe effects were noted at 1800 mg/Kg/day. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 600 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Study 2:

In another study, 14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compound. The study was performed using male and female F344 rats. The test chemical was dissolved in corn oil and used at dose level of 0,60, 125, 250, 500, or 1,000 mg/kg for 14 days. During the study, the test animals were observed for clinical signs, mortality, body weight changes and were subjected to gross and histopathology.One male rat in the 125 mg/kg group died before the end of the study. One male rat had a punctured esophagus, indicating probable gavage error. The final mean body weights of dosed male rats were 7%-12% lower than that of the controls; however, there was no clear dose related trend. The final mean body weights of the female rats were not affected in a dose related manner. No compound-related effects were observed at necropsy or after microscopic examination in either sex. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg for F344 rats when exposed for 14 days.

Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 1000 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.

Repeated dose inhalation toxicity:

Data available for the test chemicals was reviewed to determine the toxic nature of 1,4-divinylbenzene (CAS no 105-06-6). The studies are as mentioned below:

Study 1:

 Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and female Alderley Park Wistar-derived strain rats. The test chemical was generated in vapor form and exposed to animals at dose levels of0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3) for5 hr/day on 5 days/wk in stainless steel containers. During the study, the animals were observed for clinical signs, mortality, changes in body weight, food intake, water intake, hematology, clinical chemistry, urinalysis and subjected to gross and histopathology. No overt signs of exposure-related effect were reported and the mortality of the exposed rats was similar to that of the control animals throughout the study. No treatment-related changes in body weight, food and water intake. Some changes in hematology and blood chemistry parameters were observed but found to be independent of treatment. There was also no indication of an increased activity of hepatic aminopyrine demethylase. Urinary protein and coproporphyrin output was slightly elevated in tile 500-ppm group. This might have been related to functional changes in the liver or kidney, although there was no histological evidence for an effect in these organs. Liver and kidney weights were increased, giving further evidence of an effect at 500 ppm. Small increases in the weights of heart and lung tit 500 ppm were not related to any histological change and probably did not represent evidence of any effect of treatment. Bile changes in liver and kidney weights probably indicated milder manifestations of those changes seen at higher exposure levels. Apart from some suggestions of increased liver weight, no changes from control values could be discerned at the 75 -ppm level and this dose was considered to be without toxicological effect. The rats, except the controls which appeared to be normal, exhibited hemorrhagic areas in the lungs of varying degrees as well as a very bright reddish color to either one or both lungs. The heart was of normal size and color in all animals. The majority showed no liver abnormality with the exception of a few which exhibited white streaks on the surface. The kidneys appeared to be normal except for a few that were swollen. The animals showed little variation of histological change. Hyperemic and edematous areas were most frequently encountered in the lungs. The epithelium of the bronchi did not appear to be much changed in most cases. Occasionally a dissociation of the epithelium of the bronchi was seen but never very clearly. Fresh hemorrhages in the lungs were observed, mainly in the bronchi. No hypertrophy of the lymphoid tissue was noted. A pyknotic appearance of the nuclei was common. Neither damage to the cells nor hepatitis was observed in the liver sections of the rats. Some hyperemic and edematous areas were seen. All the rats showed extensive damage to the kidneys. The epithelium of the tubules was swollen in most cases. The glomeruli were swollen and hyperemic with very marked pyknosis. Almost all the tubules showed varying degrees of necrobiosis. Some animals showed degeneration and loss of alignment of the nuclei. A few of the animals showed a granular exudate in the collecting tubules. Generally the damage to the kidneys was severe. No definite heart damage was observed. Occasionally an edematous area was noted but the nuclei and striation were intact and visible. No treatment-related effect on the incidence of tumours, their multiplicity or malignancy was seen in either tile males or females exposed to test chemical vapour at levels up to 500 ppm. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 3000 mg/m3.

Study 2:

In the same study, combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using female Alderley Park derived strain mice. The test chemical was generated in vapor form and exposed to animals at dose levels of0 (air control), 75 or 500 ppm (0, 450 or 3000 mg/m3). During the study, the animals were observed for clinical signs, mortality and subjected to gross and histopathology. No overt signs of exposure-related effect were reported and the mortality of the exposed mice was similar to that of the control animals throughout the study. The mortality in the female mice did not appear to be related to the exposure. The percentage mortality for the 0-, 75- and 500-ppm exposure levels being 17, 19 and 13, respectively, at wk 52, 40, 32 and 35, respectively, at wk 72. Histopathological evaluation of the tissues of the female mice revealed a number of age-related changes. A high background incidence of respiratory disease was seen in all groups. This made the interpretation of the findings of the respiratory tract difficult to assess. However, there was no evidence of any treatment-related non-neoplastic effects in these or other tissues examined. The neoplastic lesions were of low incidence in this study. The only tumours seen in the respiratory tract were lung adenomas, which were seen at similar rates of incidence in test and control animals, and one osteosarcoma in the nasal sinus of one animal at the 75-ppm level. The incidence, localization and malignancy of these and the other types of tumours did not indicate any carcinogenic activity of p-DCB at levels up to 500 ppm in the female mice.

Based on the observations made, the NOAEC for the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is considered to be 3000 mg/m3.

Repeated dose dermal toxicity:

In accordance with coloumn 2 of Annex IX, this end point was considered for waiver since the acute toxicity by the dermal route has already been provided in section 7.2.3 (as part of the Annex VIII information requirements)

Justification for classification or non-classification

Based on the data available for the test chemicals and applying the weight of evidence approach, the test chemical 1,4-divinylbenzene (CAS no 105-06-6) is not likely to be toxic upon repeated exposure by oral and inhalation route as per the criteria mentioned in CLP regulation.