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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:
other: GLP-study according to OECD guideline 422.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

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:
no
Remarks:
Not specified
Principles of method if other than guideline:
Not applicable
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 / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle), 30, 100, 300, 1000 mg/kg/day
Basis:
actual ingested
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
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
The NOAELs for repeat dose toxicity are considered to be 30 mg/kg/day for males, and 100 mg/kg/day for females.

Detail:
[Males]
1) General condition: No death and no moribund were seen for all groups up to 1000 mg/kg/day dose.

2) Body weight: No significant difference was seen in 30 and 100 mg/kg/day groups. At 300 mg/kg/day, the significant low value was recorded on day 8 of dosing. At 1000 mg/kg/day, the significant low values was recorded during day 4 to day 50 of dosing.

3) Food consumption: At 30mg/kg/day, no significant differemce from control was seen. At 100 mg/kg/day, the significant high values were seen on day 34 and day 36. At 300 mg/kg/day, the significant high values were recorded during day 34 to day 48. At 1000 mg/kg/day, the significant low value was seen on day 3 and the high values were recorded during day 13 to day 48.

4) Hematological examination: At 30 mg/kg/day, the significant hifgh value in RBC was seen. This was not considered due to divinylbenzene dose.In 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.

5) Blood chemical examinationIn 30 and 100 mg/kg/day groups, no significant differences were seen for all items examined. At 300 mg/kg/day, the significant high value was recorded in beta-globulin. At 1000 mg/kg/day, the significant high values were recorded in GPT, gamma-GPT, alpha 2-globulin ratio, beta-globulin ratio and total bilirubin. Also the significant low values were recorded in alummin, alpha 1-globulin, alpha 3-globulin and glucose.

6) Autopsy: No abnormality was found for all groups.

7) Weight of organs: 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, the significant high value was recorded in the absolute weight of liver. At 300 mg/kg/day, the significant high value in the absolute weight of kidneys and the significant high values in the relative weight of liver and kidneys were recorded. At 1000 mg/kg/day, the significant high values were recorded in the relative weight of liver and kidneys. Although it was not the significant difference, there was the higher tendency in the absolute weight of kidneys. In addition, the significant lower values were recorded in the absolute weight of heart, spleen and testes. Also the significant high values were recorded in the relative weight of brain and testes. These, however, were not considered because of divinylbenzene dosing as there was no consstent tendency in these changes.

8) Histopathological examination: 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]
1) General condition: No death and no moribund were seen for 30, 100 and 300 mg/kg/day groups. At 1000 mg/kg/day, one death on day 17 of gestation and one moribund on day 23 of gestation during delivery were seen.

2) Body weight: Before mating period, no significant difference from control group was seen at 30, 100 and 300 mg/kg/day. At 1000 mg/kg/day, the significant 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, the significant low values were recorded on day 7 and 14 of gestation. At 1000 mg/kg/day, the significant 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, the significant low values were recorded on day 0 and day 4 of lactation.

3) Food consumption: Before mating period, no significant difference from control group was seen at 30, 100 and 300 mg/kg/day. At 1000 mg/kg/day, the significant 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, the significant low value from control group was recorded on day 21 of gestation. During lactation period, no significant difference from control groups was seen in 30,100 mg/kg/day groups. At 300 mg/kg/day, the
significant low value from control group was seen on day 4 of lactation. At 1000mg/kg/day, no significant difference was recorded, but a lower tendency were observed.

4) Weight of organs: At 30mg/kg/day, no significant difference from control group in absolute and relative weight was seen for all organs. At 100 mg/kg/day, the significant 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, the significant high value in the relative weight of kidneys were recorded. Also the 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, the significant low values were recorded in the relative and absolute weight of thymus. Also the significant 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, the significant 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.

5) Histopathological examination: At 1000 mg/kg/day groups, there were the 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).

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: No general toxicological effects observed. High relative weights of the livers were seen from the 100 mg/kg dose.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: Suppression of body weight increases and low values of the quantity of food consumed were seen in the 300 mg/kg dose.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

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