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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 4, 1997 – August 2, 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP-study according to OECD guideline 422.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of divinylbenzene and ethylstyrene
EC Number:
910-757-7
Cas Number:
N/A
Molecular formula:
Divinylbenzene: C10H10 Ethylstyrene: C10H12
IUPAC Name:
Reaction mass of divinylbenzene and ethylstyrene
Details on test material:
Source: Nippon Steel Chem.
Purity 96.2%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Males, 49 days
Females, from 14 days before mating to day 3 of lactation
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
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:
12/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
None

Examinations

Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
Terminal kill: Males, day 50; Female, day 5 of lactation
Other examinations:
None
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Males: No effects observed.

Females: One female was moribund on day 23 of gestation during delivery
Mortality:
mortality observed, treatment-related
Description (incidence):
Males: No death and no moribundity was seen for all groups up to 1000 mg/kg/day dose.

Females: No death and no moribundity were seen for 30, 100 and 300 mg/kg/day groups. At 1000 mg/kg/day, one death on day 17 of gestation was seen.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males: No significant difference was seen in 30 and 100 mg/kg/day groups. At 300 mg/kg/day, the significantly low value was recorded on day 8 of dosing. At 1000 mg/kg/day, significantly low values were recorded during day 4 to day 50 of dosing.

Females: Before mating period, no significant difference from control group was seen at 30, 100 and 300 mg/kg/day. At 1000 mg/kg/day, significantly lower values were recorded during day 4 to day 15 of dosing. During gestation period, no significant difference from control groups was seen in 30 and 100 mg/kg/day groups. At 300 mg/kg/day, significantly low values were recorded on day 7 and 14 of gestation. At 1000 mg/kg/day, significantly low values were recorded during day 0 to day 21 of gestation. During lactation period, no significant difference from control groups was seen in 30, 100 and 300 mg/kg/day groups. At 1000 mg/kg/day, significantly low values were recorded on day 0 and day 4 of lactation.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Males: At 30 mg/kg/day, no significant difference from control was seen. At 100 mg/kg/day, significantly high values were seen on day 34 and day 36. At 300 mg/kg/day, significantly high values were recorded during day 34 to day 48. At 1000 mg/kg/day, the significantly low value was seen on day 3 and the high values were recorded during day 13 to day 48.

Females: Before mating period, no significant difference from control group was seen at 30, 100 and 300 mg/kg/day. At 1000 mg/kg/day, significantly low value from control group was recorded on day 3 of dosing. During gestation period, no significant difference from control groups was seen in 30, 100 and 300 mg/kg/day groups. At 1000 mg/kg/day, significantly low value from control group was recorded on day 21 of gestation. During lactation period, no significant difference from control groups was seen in 30 or 100 mg/kg/day groups. At 300 mg/kg/day, significantly low value from control group was seen on day 4 of lactation. At 1000 mg/kg/day, no significant difference was recorded, but a lower tendency was observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Males: At 30 mg/kg/day, a significantly high value in RBC was seen. This was not considered due to divinylbenzene dose. At 100 mg/kg/day to 300 mg/kg/day groups, no significant differences were observed for all examined items. At 1000 mg/kg/day, a slightly lower value in MCHC was recorded. As the difference was very small, this was not considered as the adverse effect of DVB dosing.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Males: At 30 and 100 mg/kg/day, no significant differences were seen for all items examined. At 300 mg/kg/day, a significantly high value was recorded in beta-globulin. At 1000 mg/kg/day, significantly high values were recorded in GPT, gamma-GPT, alpha 2-globulin ratio, beta-globulin ratio and total bilirubin. Also, significantly low values were recorded in alummin, alpha 1-globulin, alpha 3-globulin and glucose.
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Males: At 30 mg/kg/day, no significant difference from control group in absolute and relative weight was seen for all organs. At 100 mg/kg/day, a significantly high value was recorded in the absolute weight of liver. At 300 mg/kg/day, significantly high value in the absolute weight of kidneys and significantly high values in the relative weight of liver and kidneys were recorded. At 1000 mg/kg/day, significantly high values were recorded in the relative weight of liver and kidneys. Although it was not a significant difference, there was a higher tendency in the absolute weight of kidneys. In addition, significantly lower values were recorded in the absolute weight of heart, spleen and testes. Also, significantly high values were recorded in the relative weight of brain and testes. These, however, were not considered caused by divinylbenzene dosing as there was no consistent tendency in these changes.

Females: At 30 mg/kg/day, no significant difference from control group in absolute and relative weight was seen for all organs. At 100 mg/kg/day, significantly low value was recorded in the absolute weight of adrenal glands. However, this was not considered to be the adverse effects of DVB dosing because no consistent trend was found between absolute and relative weight changes. At 300 mg/kg/day, significantly high value in the relative weight of kidneys were recorded. Also, low values of heart and adrenal grands were seen. This was considered not because of DVB dosing since no consistent trend was found between absolute and relative weight changes. At 1000 mg/kg/day, significantly low values were recorded in the relative and absolute weight of thymus. Also, significantly low values of absolute spleen weight, a lower tendency of relative spleen weight and the significant high values in the absolute weight of liver, kidneys and adrenal glands were seen. In addition, significantly low values in absolute weight of brain, pituitary and heart, and the significant high values in brain and ovaries, were observed. These, however, were considered not due to DVB dosing because no consistent tendency was found between absolute and relative weight changes.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Males: Although slight changes were observed in liver, testis and epididymis, these changes were not considered caused by the dose of divinylbenzene because the control group showed the same changes and the number of animals with these changes were small.

Females: At 1000 mg/kg/day, there were significant differences from control group as follows: Atrophy of the thymus (7 of 10 examined), atrophy of the marginal zone in the spleen (2 of 10 examined) and degeneration/necrosis of the renal tuble of cortico- medullary junction in the kidney (3 of 10 examined).
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
The NOAELs for repeat dose toxicity are considered to be 30 mg/kg/day for males, and 100 mg/kg/day for females.
Executive summary:

This study was conducted in accordance with OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) in male and female rats at daily oral doses of 30, 300, and 1000 mg/kg.

 

In males, no death and no moribundity were seen for all groups up to 1000 mg/kg/day dose. Significantly reduced body weights and food consumption were observed at300 mg/kg. Increased relative liver weights were observed at100 mg/kg and increased relative kidney weights were observed at300 mg/kg.

 

In females, at 1000 mg/kg, one animal died on day 17 of gestation and one was found moribund on day 23 of gestation during delivery. Suppressed body weights and food consumption were observed at300 mg/kg.

 

The NOAELs for repeat dose toxicity are considered to be 30 mg/kg/day for males, and 100 mg/kg/day for females.