1,4-divinylbenzene

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Data source

Reference

Reference Type:

publication

Title:

Repeated dose inhalation toxicity study of the test chemical

Author:

Loeser and Litchfield

Year:

1983

Bibliographic source:

Fd Chem. Toxic.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Repeated dose inhalation toxicity study was conducted to determine the toxic nature of the test chemical

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4-dichlorobenzene

EC Number:

203-400-5

EC Name:

1,4-dichlorobenzene

Cas Number:

106-46-7

Molecular formula:

C6H4Cl2

IUPAC Name:

1,4-dichlorobenzene

Details on test material:

- Name of test material: p-Dichlorobenzene- Molecular formula: C6H4Cl2- Molecular weight: 147.0036 g/mol- Substance type: Organic- Physical state: White crystalline compound- Impurities (identity and concentrations): No data

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Alderley Park Wistar-derived strain

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: SPF- Age at study initiation:- Weight at study initiation: 150-300 g- 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

Administration / exposure

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 p-DCB (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: The exposure levels were monitored ever 2 3 days rising an infra-red analyser. The overall deviation from themean levels was less than 2%- 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 or 100 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:

76 weeks

Frequency of treatment:

5 hr/day on 5 days/wk

Doses / concentrations

Remarks:

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

No. of animals per sex per dose:

76-79 rats of both sexes

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

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 data

Sacrifice and pathology:

GROSS 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.

Other examinations:

Samples of fat, liver, plasma and urine from selected animals ere analysed for metabolites of at wk 26 and 76 and at the termination of the study

Statistics:

No data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No overt signs of exposure-related effect were reported

Mortality:

no mortality observed

Description (incidence):

The mortality of the exposed rats was similar to that of the control animals throughout the study

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related changes in body weight

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

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):

No treatment-related changes in water intake

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

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

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

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:

effects observed, non-treatment-related

Description (incidence and severity):

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:

effects observed, non-treatment-related

Description (incidence and severity):

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. File 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

Gross pathological findings:

no effects observed

Description (incidence and severity):

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:

not specified

Description (incidence and severity):

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. enerally 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.

Description (incidence and severity):

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.

Other effects:

not specified

Details on results:

No data

Effect levels

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

Remarks on result:

other: No effect observed

Target system / organ toxicity

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

Applicant's summary and conclusion

Conclusions:

The No observed adverse effect level (NOAEL) for the test chemical is considered to be 3000 mg/m3.

Executive summary:

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.