2,3-epoxybutane

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well-documented report, comparable to guideline/standards

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Reference 2

Reference Type:

publication

Title:

Respiratory tract lesions in F344/N rats and B6C3F1 mice after inhalation exposure to 1,2-epoxybutane.

Author:

Dunnick, J.K., Eustis, S.L., Piegorsch, W., Miller, A.

Year:

1988

Bibliographic source:

Toxicology 50, 69 - 82

Materials and methods

Principles of method if other than guideline:

according to internal NTP guidelines

GLP compliance:

yes

Remarks:

testing lab.

Test material

Test material information

Constituent 1

Reference substance name:

1,2-epoxybutane

EC Number:

203-438-2

EC Name:

1,2-epoxybutane

Cas Number:

106-88-7

Molecular formula:

C4H8O

IUPAC Name:

2-ethyloxirane

Details on test material:

1,2-epoxybutane - purity > 99%; impurity: 1,2-butanediol

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female rats used in this study were produced under strict barrier conditions at Charles River Breeding Laboratories under a contract to the Carcinogenesis Program. Breeding stock for the foundation colonies at the production facility originated at the National Institutes of Health Repository. Animals shipped for study were progeny of defined microflora-associated parents that were transferred from isolators to barrier-maintained rooms. Animals were shipped to the study laboratory at 4-6 weeks of age and were quarantined for 3 weeks. Thereafter, a complete necropsy was performed on five animals of each sex and species to assess their health status. The ratss were placed on study at 7-9 weeks of age.
All animals were housed individually in Hazleton chambers throughout the study. Feed and water were available ad libitum except during exposure periods; water was available at all times.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: room air

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

-

Doses / concentrations

Remarks:

Doses / Concentrations:
200, 400 ppm (0.598, 1.197 mg/l)
Basis:
nominal conc.

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

Because of the lower body weight gain and nasal cavity inflammation at 800 ppm, 1,2-epoxybutane concentrations selected for rats for the 2-year studies were 200 and 400 ppm.

Examinations

Observations and examinations performed and frequency:

Body weights and clinical signs, survival, nasal cavity, lung, hematopoietic system, thyroid gland, anterior pituitary gland, preputial gland.
All animals were observed two times per day, and clinical signs were recorded once per month. Individual body weights were recorded once per week for the first 13 weeks of the studies and once per month thereafter. Mean body weights were calculated for each group. Animals found moribund and those surviving to the end of the studies were humanely killed.

Sacrifice and pathology:

A necropsy was performed on all animals including those found dead, unless they were excessively autolyzed or cannibalized, missexed, or found missing. Thus, the number of animals from which particular organs or tissues were examined microscopically varies and is not necessarily equal to the number of animals that were placed on study.
During necropsy, all organs and tissues were examined for grossly visible lesions. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.
Necropsy and histologic examination performed on all animals; the following tissues examined: adrenal glands, brain, clitoral or preputial gland, colon, esophagus, gross lesions and tissue masses, heart, kidneys, lungs and mainstem bronchi, mammary gland, mandibular lymph nodes, nasal cavity and nasal turbinates, pancreas, parathyroids, pituitary gland, prostate, testes, epididymis or ovaries/uterus, rectum, regional lymph nodes, salivary glands, skin. small intestine, spleen, sternebrae including marrow, stomach. thymus, thyroid gland, trachea, tracheobronchial lymph nodes, and urinary bladder.

Statistics:

Differences in survival were analyzed by life-table methods. Tumor incidence data were analyzed by survival-adjusted methods and by Fisher's exact tests and Cochran-Armitage trend tests based on the overall proportion of tumor-bearing animals. Non-neoplasatic incidence data were analyzed by Fisher's exact test.

Results and discussion

Results of examinations

Details on results:

Body Weights and Clinical Signs: Mean body weights of exposed and control male rats were similar until week 86; thereafter, mean body weights of high dose male rats were 4%-8% lower than those of the controls. Mean body weights of high dose female rats were 5%-10% lower than those of the controls after week 22. No compound-related clinical signs were observed in either males or females.
Survival: The survival of the low dose groups of both male (after week 101) and female (after week 90) rats was significantly lower than that of the control groups.
Nasal Cavity: Suppurative and serous inflammation, hyperplasia of the respiratory epithelium, and squamous metaplasia were observed at increased incidences in exposed male and female rats. Suppurative inflammation was characterized by the presence of neutrophils within the nasal cavity and mucosa; serous inflammation consisted of an eosinophilic protein-aceous material containing few inflammatory cells within the lumen of the nasal cavity. Other inflammatory lesions with lymphocyte and macrophage infiltrates were diagnosed as unspecified inflammation. Epithelial hyperplasia consisted of diffuse crowding of epithelial cells and increased thickness of the respiratory epithelium. In focal areas, nodular proliferation of respiratory epithelium formed glandlike structures that were diagnosed as adenomatous hyperplasia. Squamous metaplasia was a focal or multifocal lesion that occurred frequently within the respiratory epithelium, especially in the anterior section of the nasal cavity. Atrophy of the olfactory sensory epithelium was observed at increased incidences in exposed male and female rats. Hyperostosis of the nasal turbinate bone, consisting of a periosteal cell proliferation and new bone formation, was observed at increased frequency in high dose male rats. The incidence of papillary adenomas in high dose male rats was significantly greater than that in the controls. These tumors were exophytic papillary growths of a cuboidal to columnar nonciliated epithelium which were attached to the underlying mucosa by thin stalks or broad bases. There was no evidence of local invasive growth by these adenomas. Papillary adenomas were observed in two high dose female rats.
Lung: Alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined) in male rats occurred with significant positive trends; the incidences in the high dose group were significantly greater than those in the controls. The incidences of adenomas or carcinomas (combined) in female rats were as follows: control 2/50, low dose 0/49, high dose 1/150.
Hematopoietic System: The incidence of mononuclear cell leukemia was significantly greater by the life table test (P=0.011) in low dose (but not in high dose) male rats than that in the controls (control, 25/50; low dose, 31/50; high dose, 22/50).
Thyroid Gland: Follicular cell adenomas or carcinomas (combined) in female rats occurred with a significant positive trend by the life table test (P=0.043) but not by the incidental tumor test (the more appropriate test for analysis of these nonfatal tumors); the incidences in the dosed groups were not significantly greater than that in the controls (control, 0/45; low dose, 1/48; high dose, 3/48). Follicular cell hyperplasia was not observed in either control or high dose rats.
Anterior Pituitary Gland: Adenomas in female rats occurred with a signficant positive trend, 1 and the incidence in the high dose group was significantly greater than that in the controls. The incidences of adenomas or carcinomas (combined) are significant by the life table test but not by the incidental tumor test (the latter test is considered more appropriate for analysis of nonfatal tumors).
Preputial Gland: The incidences of adenomas, carcinomas, or squamous cell carcinomas (combined) in male rats (control, 3/50; low dose, 3/50; high dose, 8/50) were marginally significant by the life table trend test (P= 0.050) but not by the incidental tumor trend test (the more appropriate test for analysis of these non-fatal tumors). The incidence in the high dose group was not signicantly greater than that in the controls.

Effect levels

1

Dose descriptor:

NOEC

Effect level:

200 ppm

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Effect type: toxicity (migrated information)

2

Dose descriptor:

LOEC

Effect level:

400 ppm

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Effect type: toxicity (migrated information)

Any other information on results incl. tables

Exposure-related non-neoplastic and neoplastic lesions in the nasal cavity and lung of rats exposed to 1.2-Epoxybutane for 2 years

Lesions	Incidence
	Male rats			Female rats
	0 ppm	200 ppm	400 ppm	0 ppm	200 ppm	400 ppm
Nasal cavity
- inflammation (unspecified)	9	36	42	25	32	43
- serious inflammation	2	28	36	0	18	31
- suppurative inflammation	10	37	49	6	26	45
- hyperostosis	0	2	11	0	2	16
- epithelial hyperplasia	8	38	46	5	29	40
- adenomatous hyperplasia	0	0	5	0	0	2
- squamous metaplasia	4	22	40	1	14	36
- papillary adenoma	0	0	7	0	0	2
Olfactory sensory epthelium
- atrophy	0	18	12	0	13	8
Lung (alveolar/bronchiolar)
- epithelial hyperplasia	5	5	8	2	6	7
- adenoma	0	1	1	1	0	1
- carcinoma	0	1	4	1	0	0
- adenoma or carcinoma	0	2	5	2	0	1

Based on 50 animals examined in each group; lung tumor rates for males at 400 ppm based on 49 animals.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the 2-year inhalation study, there was clear evidence of carcinogenic activity of the test substance for male F344/N rats, as shown by an increased incidence of papillary adenomas of the nasal cavity, alveolar/bronchiolar carcinomas, and alveolar/bronchiolar adenomas or carcinomas (combined). There was equivocal evidence of carcinogenic activity for female F344/N rats, as shown by the presence of papillary adenomas of the nasal cavity.