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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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:
other: Acceptable, well documented publication which meets basic scientific principles
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Rat and Mouse Forestomach Tumors Induced by Chronic Oral Administration of Styrene Oxide
Author:
Lijinski
Year:
1986
Bibliographic source:
JNCI 1986; 77:471-476
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
, many inlife-investigations not performed, no daily dosing
GLP compliance:
no
Remarks:
some parts performed under quality assurance
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9 weeks
- Weight at study initiation: females 126-157 g, males 178-241 g
- Fasting period before study:
- Housing: 5 per cage
- Acclimation period: 2 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatographic analysis showed that the concentrations were as stated within very close limits and that the solutions displayed no change upon storage for 72 hours
Duration of treatment / exposure:
24 weeks (interim sacrifices at 5, 10, and 15 weeks)
Frequency of treatment:
three times a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 180, 360, 750, 1500, and 3000 mg/kg/3 time per week
Basis:
actual ingested
No. of animals per sex per dose:
10 (further 12 rats in 1500 and 360 mg/kg/day dose group for 3 interim kills of 4 animals each)
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Mortality
body weight
Sacrifice and pathology:
Histopathologic evaluation of organs, no further data
Statistics:
Fisher's exact probability test and Cochran-Armitage test for positive trend

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Diffuse liver cell hyperplasia
Basal cell hyperplasia and/or hyperkeratosis of the forestomach

Effect levels

open allclose all
Dose descriptor:
LOEL
Effect level:
180 mg/kg bw/day (nominal)
Based on:
not specified
Sex:
male/female
Basis for effect level:
other: hyperplasie, administration 3 times per weeek
Dose descriptor:
LOEL
Effect level:
77 mg/kg bw/day (nominal)
Based on:
other: time corrected
Sex:
male/female
Basis for effect level:
other: corrected 3 days/7days

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A NOAEL could not be determined due to basal cell hyperplasia and/or hyperkeratosis in all treated dose groups. A MTD of 500 mg/kg bw was established.
Executive summary:

In a sub-chronic study, groups of 10 male and 10 female F344 rats were given doses of styrene oxide (in corn oil) corresponding to 3000, 1500, 750, 360 and 180 mg/kg bw three times a week. A control group was given only corn oil. These groups were treated for 24 weeks. In addition 12 rats of each sex were given 1500 or 360 mg/kg bw for interim sacrifice of 4 rats at 5, 10, and 15 weeks of the study; 12 additional controls given vehicle were also used for interim sacrifice.

 

Decrease survival was seen in the rats given the highest dose of styrene oxide. Of the rats given 3000 mg/kg bw 30 % of the males dies in the first 5 weeks and 40 % of the females died in the first 5 weeks; all were dead at 10 weeks. Of the rats given 1500 mg/kg bw 20 % of the females and 30 % of the males died at 24 weeks. Histopathologic examination of the animals revealed basal cell hyperplasia and hyperkeratosis of the forestomach and lesions in the liver, including hemorrhagic necrosis in those that died; several rats also had renal tubular epithelial degeneration or necrosis. Among the rats given lower doses, all of which survived, the changes observed histologically were some degree of liver cell hyperplasia, which varied from mild to moderate, and renal tubular degeneration in a few cases. There was no significant depression of weight gain among the animals receiving the three lowest doses of styrene oxide, but there was some decrease (> 10 %) at the two highest doses. The diffuse liver cell hyperplasia was somewhat greater in the group of rats given 750 mg/kg bw styrene oxide than in the group given 360 mg/kg bw styrene oxide in which it was only mild at most.

A MTD of 500 mg/kg bw was established by the study author for the development of a chronic carcinogenicity study.