(epoxyethyl)benzene

Repeated dose toxicity: oral

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 for cross-reference:

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

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study 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

Test material information

Constituent 1

Reference substance name:

(epoxyethyl)benzene

EC Number:

202-476-7

EC Name:

(epoxyethyl)benzene

Cas Number:

96-09-3

Molecular formula:

C8H8O

IUPAC Name:

2-phenyloxirane

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system 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

1

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

2

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.