Divinylbenzene

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

The No observed adverse effect level (NOAEL) for the test chemical Divinylbenzene (CAS no 1321-74-0) 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 Divinylbenzene (CAS no 1321-74-0) 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:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data from J- check

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Repeated oral administration toxicity / reproductive developmental toxicity combined study of test material was performed on rats

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Japan- Age at study initiation: 8-week-old- Weight at study initiation: Males :315 to 352 g Females :211 to 239 g- Fasting period before study:- Housing: stainless steel cages were used to keep up to 5 groups per cage. In addition, the mother animals were individually transferred to a plastic cage containing autoclaved bedding (Sunflake, Japan CharlesRiver ) on the 18th day of pregnancy,- Use of restrainers for preventing ingestion (if dermal): yes/no- Diet (e.g. ad libitum): solid feed (CRF- 1, Oriental Yeast Co., Ltd. ), ad libitum- Water (e.g. ad libitum): drinking water was freely ingested in tap water. ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C):20 to 24 ° C.- Humidity (%):40 to 70%,- Air changes (per hr):12 times / hour- Photoperiod (hrs dark / hrs light):light and darkeach for 12 hours (lighting: 6 am to 6 pm)

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:The test substance was prepared by diluting it with corn oil.DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): test material soluble corn oil- Concentration in vehicle: 0, 30, 100, 300 and1000 mg / kg- Amount of vehicle (if gavage): 5 ml/kg- Lot/batch no. (if required): No data available- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males, day 50Females, day 4 of lactation

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

30 mg/kg bw/day (actual dose received)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Total:1200 mg/kg bw/day: 12 male and 12 females30mg/kg bw/day:12 male and 12 females100mg/kg bw/day:12 male and 12 females300 mg/kg bw/day:12 male and 12 females1000 mg/kg bw/day:12 male and 12 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed.

Positive control:

not specified

Observations and examinations performed and frequency:

Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yesDETAILED CLINICAL OBSERVATIONS: YesTime schedule: They were observed daily for mortality and clinical signs of toxicity.BODY WEIGHT: YesTime schedule for examinations: male: Body weight was measured twice a week.Female: Body weights were measured 14 days before the mating and twice weekly during the mating period, on 0, 7, 14 and 21 gestation during gestation, on 0 and 4 nursing during the feeding period, res pectivelyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. Also, during pregnancy, gestation was measured on 2, 9, 16 and 21 gestation, and during nursing during 4 days of nursing.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: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No dataTime schedule for examinations:OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified- Time schedule for examinations:- Dose groups that were examined:HAEMATOLOGY: Yes - Time schedule for collection of blood:At the end of the administration period. - Anaesthetic used for blood collection: Yes, sodium pentobarbital- Animals fasted: Not specified- How many animals:All - Parameters checked in table [No.?] were examined. red blood cell count (RBC), the hemoglobin amount, the hematocrit value, the platelet count and the white blood cell count (WBC), mean red blood cell volume (MCV), mean red blood cell hemoglobin amount (MCH) and mean red blood cell hemoglobin concentration (MCHC), Prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen concentration were examined. CLINICAL CHEMISTRY: Yes - Time schedule for collection of blood:At the end of the administration period. - Animals fasted: Not specified- How many animals: All - Parameters checked in table [No.?] were examined. GOT and GPT, ALP, γ-GTP, total protein, total bilirubin, urea nitrogen (BUN), glucose, total cholesterol, triglyceride, Ca, inorganic phosphorus, Na and K, Cl, albumin, A / G ratio were examined. OTHER:Organ weight:The brain (cerebrum, cerebellum, medulla oblongata), pituitary gland, thyroid, thymus, heart, liver, spleen, kidney, adrenal glands, testicles and epididymis were weighed.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, gross pathological examined were performed on all the organs. HISTOPATHOLOGY: Yes, Paraffin-embedded specimens were prepared for the excised organs and tissues according to a conventional method. In the control group and the 1000 mg / kg group of heart, lung, trachea, liver, pancreas, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, thymus, spleen, lymph node (mandibular mesentery), kidney, adrenal gland , Bladder, testis, epididymis, seminal vesicle, prostate, pituitary gland, thyroid, parathyroid gland (only for testable animals), brain (cerebrum / cerebellum / medulla oblongata), spinal cord, sciatic nerve and bone marrow ), HE - stained tissue specimens were prepared and examined histopathologically.

Statistics:

For the significant difference test, a homogeneous distribution test by the Bartlett method, and if it is equipartised, a variance analysis is performed by the one-way method, and if it is significant, it is done by the Dunnett method. On the other hand, in the case where it was not recognized as equal variance, weperformed analysis by one-way method using rank order (Kruskal-Wallis test), and if significant, use Dunnett type test method using ranking.

Clinical signs:

no effects observed

Description (incidence and severity):

No abnormalities were observed in any animals throughout the observation period in the control group. Salivation was observed after administration in groups above 30 mg / kg. In the 1000mg / kg group, skin temperature warming and depilation were observed in one case and contamination of the coat in 1 to 8 cases. Salivation was observed in each group up to about 30 minutes after administration, and no change was observed in salivation duration even when administration was continued. Damage to the incisors was observed in the 100 mg / kg group, but only one case was found and it was judged as a contingent case

Mortality:

mortality observed, non-treatment-related

Description (incidence):

for male: Death and moribund cases were not observed in either group.For female animals, one case of death and one case of moribund were observed in the 1000 mg / kg group

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The body weights of the 30 and 100 mg / kg group were almost the same as those of the control group.In the 300 mg / kg group, the body weight was significantly lower on the 8th day of administration than in the control group. In the 1000 mg / kg group, there was a significant lower value of body weight on 4 to 50 days of administration than in the control group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The food consumption of the 30 mg / kg group was almost the same as that of the control group.In the 100 mg / kg group, a significant increase in food intake was observed on Days 34 and 38 compared to the control group. In the 300 mg / kg group, a significant increase in food intake was observed on the 34th to 48 th day of administration compared with the control group. In the 1000 mg / kg group, a significant low value of food intake was found on the 3rd day of administration compared to the control group, and a significant high value of food intake was observed on the 13th to 48th days of administration.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

In the 30 mg / kg group, a significant high value of erythrocyte count was seen compared with the control group, but it was judged that it was not a dose dependent change and not based on administration. In the 100 and 300 mg/ kg group, there was no significant difference in any measurement items compared with the control group. In the 1000 mg / kg group, a significant lower value of MCHC was found compared to the control group, but it was judged that it is a mild difference and not based on administration.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

In the 30 and 100 mg / kg group, there was no significant difference in any of the measurement items compared to the control group. In the 300 mg / kg group, a significant high value of β - globulin rate was found compared with the control group. In the 1000 mg / kg group, compared to the control group, there was a significant increase in GPT, γ-GTP, α 2 -globulin ratio, β-globulin ratio and total high bilirubin value, albumin amount, α 1 -globulin rate, α 3 -globulin rate and blood glucose Significantly low values were observed.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

In the 30 mg / kg group, there was no significant difference in absolute weight and relative weight of any organ compared to the control group. In the 100 mg / kg group, a significant elevation of the relative weight of the liver was observed compared to the control group. In the 300 mg / kg group, a significant high value of the absolute weight of the kidney as well as a significant high value of the relative weight of the liver and kidney was observed compared to the control group. In the 1000 mg / kg group, the relative weights of the liver and kidney were significantly higher than the control group, and there was no significant difference, but the absolute weight tendency of the kidney was high. Besides, in the 1000 mg /kg group, significant lower values of the absolute weights of the heart, spleen and epididymis as compared with the control group, and significant higher values of relative weights of the brain and testis were observed The change in absolute weight and relative weight was not found to have a certain tendency, so it was judged that it was not based on administration.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There was no abnormality in any of the control group, 30, 100 and 300 mg / kg group. In the 1000 mg /kg group, dark red spots of glandular gastric mucosa were found in one case but judged as a contingent case.At necropsy of surviving cases, no abnormality was observed in the control group and 300 mg /kg group. At 30 mg / kg group, thymus atrophy was found in one case. In the 100 mg / kg group, ulcers of the forestomachial mucosa were found in one case. In the 1000 mg / kg group, whitening of the adrenal glands on both sides occurred in 1 case and atrophy of the thymus was seen in 7 cases. Thymus atrophy was observed at necropsy of deaths in the 1000 mg / kg group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Necrotic necrosis of the liver, seminiferous tube atrophy of the testes, and sperm granulomas of the epididymis were observed, but they were judged as accidental changes because they were seen at the same degree in the control group or in a small number.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

NOAEL was considered to be 1000 mg/kg bw when Sprague-Dawley male and female rats were treated with Divinylbenzene orally by gavage for day 50 in male and till day 4 of lactation for female.

Executive summary:

In a c Combined Repeat Dose and Reproductive / Developmental Toxicity Screening Test, Sprague-Dawley male and female rats were treated with Divinylbenzene in the concentration of 0, 30, 100, 300 and 1000 mg/kg bw orally by gavage for day 50 in male and till day 4 of lactation for female. No abnormalities were observed in any animals throughout the observation period in the control group. Salivation was observed after administration in groups above 30 mg / kg. In the 1000mg / kg group, skin temperature warming and depilation were observed in one case and contamination of the coat in 1 to 8 cases. Salivation was observed in each group up to about 30 minutes after administration, and no change was observed in salivation duration even when administration was continued. Damage to the incisors was observed in the 100 mg / kg group, but only one case was found and it was judged as a contingent case. Death and moribund cases were not observed in either group in male rat. One case of death and one case of moribund were observed in the 1000 mg / kg group in female rats. The body weights at 30 and 100 mg / kg group were almost the same as those of the control group. In the 300 mg / kg group, the body weight was significantly lower on the 8^thday of administration than in the control group. In the 1000 mg / kg group, there was a significant lower value of body weight on 4 to 50 days of administration than in the control group. The food consumption of the 30 mg / kg group was almost the same as that of the control group. In the 100 mg / kg group, a significant increase in food intake was observed on Days 34 and 38 compared to the control group. In the 300 mg / kg group, a significant increase in food intake was observed on the 34th to 48 th day of administration compared with the control group. In the 1000 mg / kg group, a significant low value of food intake was found on the 3rd day of administration compared to the control group, and a significant high value of food intake was observed on the 13th to 48th days of administration. Similarly, In the 30 mg / kg group, a significant high value of erythrocyte count was seen compared with the control group, but it was judged that it was not a dose dependent change and not based on administration. In the 100 and 300 mg/ kg group, there was no significant difference in any measurement items compared with the control group. In the 1000 mg / kg group, a significant lower value of MCHC was found compared to the control group, but it was judged that it is a mild difference and not based on administration. In the 30 and 100 mg / kg group, there was no significant difference in any of the measurement items compared to the control group. In the 300 mg / kg group, a significant high value of β - globulin rate was found compared with the control group. In the 1000 mg / kg group, compared to the control group, there was a significant increase in GPT, γ-GTP, α 2 -globulin ratio, β-globulin ratio and total high bilirubin value, albumin amount, α 1 -globulin rate, α 3 -globulin rate and blood glucose significantly low values were observed. In addition, in the 30 mg / kg group, there was no significant difference in absolute weight and relative weight of any organ compared to the control group. In the 100 mg / kg group, a significant elevation of the relative weight of the liver was observed compared to the control group. In the 300 mg / kg group, a significant high value of the absolute weight of the kidney as well as a significant high value of the relative weight of the liver and kidney was observed compared to the control group. In the 1000 mg / kg group, the relative weights of the liver and kidney were significantly higher than the control group, and there was no significant difference, but the absolute weight tendency of the kidney was high. Besides, in the 1000 mg /kg group, significant lower values of the absolute weights of the heart, spleen and epididymis as compared with the control group, and significant higher values of relative weights of the brain and testis were observed The change in absolute weight and relative weight was not found to have a certain tendency, so it was judged that it was not based on administration. There was no abnormality in any of the control group, 30, 100 and 300 mg / kg group. In the 1000 mg /kg group, dark red spots of glandular gastric mucosa were found in one case but judged as a contingent case. At necropsy of surviving cases, no abnormality was observed in the control group and 300 mg /kg group. At 30 mg / kg group, thymus atrophy was found in one case. In the 100 mg / kg group, ulcers of the fore stomachial mucosa were found in one case. In the 1000 mg / kg group, whitening of the adrenal glands on both sides occurred in 1 case and atrophy of the thymus was seen in 7 cases. Thymus atrophy was observed at necropsy of deaths in the 1000 mg / kg group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. Necrotic necrosis of the liver, seminiferous tube atrophy of the testes, and sperm granulomas of the epididymis were observed, but they were judged as accidental changes because they were seen at the same degree in the control group or in a small number. Therefore, NOAEL was considered to be 1000 mg/kg bw when Sprague-Dawley male and female rats were treated with Divinylbenzene orally by gavage for day 50 in male and till day 4 of lactation for female.

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 Divinylbenzene (CAS no 1321-74-0). The studies are as mentioned below:

In a c Combined Repeat Dose and Reproductive / Developmental Toxicity Screening Test, Sprague-Dawley male and female rats were treated with Divinylbenzene in the concentration of 0, 30, 100, 300 and 1000 mg/kg bw orally by gavage for day 50 in male and till day 4 of lactation for female. No abnormalities were observed in any animals throughout the observation period in the control group. Salivation was observed after administration in groups above 30 mg / kg. In the 1000mg / kg group, skin temperature warming and depilation were observed in one case and contamination of the coat in 1 to 8 cases. Salivation was observed in each group up to about 30 minutes after administration, and no change was observed in salivation duration even when administration was continued. Damage to the incisors was observed in the 100 mg / kg group, but only one case was found and it was judged as a contingent case. Death and moribund cases were not observed in either group in male rat. One case of death and one case of moribund were observed in the 1000 mg / kg group in female rats. The body weights at 30 and 100 mg / kg group were almost the same as those of the control group. In the 300 mg / kg group, the body weight was significantly lower on the 8^thday of administration than in the control group. In the 1000 mg / kg group, there was a significant lower value of body weight on 4 to 50 days of administration than in the control group. The food consumption of the 30 mg / kg group was almost the same as that of the control group. In the 100 mg / kg group, a significant increase in food intake was observed on Days 34 and 38 compared to the control group. In the 300 mg / kg group, a significant increase in food intake was observed on the 34th to 48 th day of administration compared with the control group. In the 1000 mg / kg group, a significant low value of food intake was found on the 3rd day of administration compared to the control group, and a significant high value of food intake was observed on the 13th to 48th days of administration. Similarly, In the 30 mg / kg group, a significant high value of erythrocyte count was seen compared with the control group, but it was judged that it was not a dose dependent change and not based on administration. In the 100 and 300 mg/ kg group, there was no significant difference in any measurement items compared with the control group. In the 1000 mg / kg group, a significant lower value of MCHC was found compared to the control group, but it was judged that it is a mild difference and not based on administration. In the 30 and 100 mg / kg group, there was no significant difference in any of the measurement items compared to the control group. In the 300 mg / kg group, a significant high value of β - globulin rate was found compared with the control group. In the 1000 mg / kg group, compared to the control group, there was a significant increase in GPT, γ-GTP, α 2 -globulin ratio, β-globulin ratio and total high bilirubin value, albumin amount, α 1 -globulin rate, α 3 -globulin rate and blood glucose significantly low values were observed. In addition, in the 30 mg / kg group, there was no significant difference in absolute weight and relative weight of any organ compared to the control group. In the 100 mg / kg group, a significant elevation of the relative weight of the liver was observed compared to the control group. In the 300 mg / kg group, a significant high value of the absolute weight of the kidney as well as a significant high value of the relative weight of the liver and kidney was observed compared to the control group. In the 1000 mg / kg group, the relative weights of the liver and kidney were significantly higher than the control group, and there was no significant difference, but the absolute weight tendency of the kidney was high. Besides, in the 1000 mg /kg group, significant lower values of the absolute weights of the heart, spleen and epididymis as compared with the control group, and significant higher values of relative weights of the brain and testis were observed The change in absolute weight and relative weight was not found to have a certain tendency, so it was judged that it was not based on administration. There was no abnormality in any of the control group, 30, 100 and 300 mg / kg group. In the 1000 mg /kg group, dark red spots of glandular gastric mucosa were found in one case but judged as a contingent case. At necropsy of surviving cases, no abnormality was observed in the control group and 300 mg /kg group. At 30 mg / kg group, thymus atrophy was found in one case. In the 100 mg / kg group, ulcers of the fore stomachial mucosa were found in one case. In the 1000 mg / kg group, whitening of the adrenal glands on both sides occurred in 1 case and atrophy of the thymus was seen in 7 cases. Thymus atrophy was observed at necropsy of deaths in the 1000 mg / kg group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. Necrotic necrosis of the liver, seminiferous tube atrophy of the testes, and sperm granulomas of the epididymis were observed, but they were judged as accidental changes because they were seen at the same degree in the control group or in a small number. Therefore, NOAEL was considered to be 1000 mg/kg bw when Sprague-Dawley male and female rats were treated with Divinylbenzene orally by gavage for day 50 in male and till day 4 of lactation for female.

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.

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 Divinylbenzene (CAS no 1321-74-0) is considered to be 1000 mg/Kg/day. Hence the test chemical is not likely to classify as repeated dose oral toxic as per the criteria mentioned in CLP regulation.

Repeated dose inhalation toxicity:

Data available for the test chemicals was reviewed to determine the toxic nature of Divinylbenzene (CAS no 1321-74-0). 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 Divinylbenzene (CAS no 1321-74-0) 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 Divinylbenzene (CAS no 1321-74-0) is not likely to be toxic upon repeated exposure by oral and inhalation route as per the criteria mentioned in CLP regulation.