1,2-epoxybutane

Carcinogenicity

Description of key information

Under the conditions of a 2-year inhalation study, there was 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. The NOAEC was 200 ppm. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed for 2 years at 50 or 100 ppm test item vapours.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

A 2-year inhalation exposure study was performed according to internal NTP guidelines.

GLP compliance:

yes

Remarks:

testing lab.

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 8-9 wk
- Weight at study initiation: ca. 24 g (males), ca. 20 g (females)
- Housing: Stainless steel wire bottom cages, 1 per cage
- Diet: Feed was available ad libitum during non-exposure periods. NIH 07 Rat and Mouse Ration (Zeigler Bros., Gardners, PA)
- Water: ad libitum
- Acclimation period: 20-21 days

DETAILS OF FOOD AND WATER QUALITY: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 71-79°F
- Humidity (%): 43-69 during exposure, mean of 43% during non-exposure
- Air changes (per hr): 10 during exposure/20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: room air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The liquid to be vaporized was contained in a 1.6-liter stainless steel reservoir housed in a vapor hood in the exposure room. The liquid was pumped from this reservoir to a stainless steel cylinder covered with a glass fiber wick from which the liquid was vaporized. An 80-watt heater and a temperature-sensing element were incorporated within the cylinder. The heater maintained the vaporizer at approximately 58°C. The surface temperature of the vaporizer was slightly lower. To minimize material loss due to condensation on duct walls, each cylindrical vaporizer was positioned in the fresh air duct leading directly into the exposure chamber.
Uniformity of vapor concentration in each exposure chamber was measured with a portable photoionization detector periodically throughout the studies. The data showed that when expressed as a percentage of the normalized average concentration of all 12 sampling positions, the standard deviation did not exceed 5% for all but two measurements. (For those two measurements, the standard deviation was within 10%.)
Samples of the atmosphere in the 1,2-epoxybutane exposure chamber were examined for the occurrence of potential degradation products, specifically 1,2-butandiol. Through the use of a Hewlett Packard model 5840A gas chromatograph equipped with a flame ionization detector and a 6 ft x 4 mm 1D glass column packed with 10% Carbowax 20M on 801100 Chromosorb WAW, a single homogeneous peak was observed; no evidence for any degradation was detected. It is concluded from this study that the 1,2-epoxybutane vapor generated during these studies was at least 99% pure.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

102 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

no

Dose / conc.:

50 ppm (nominal)

Remarks:

0.15 mg/L (nominal)

Dose / conc.:

100 ppm (nominal)

Remarks:

0.3 mg/L (nominal)

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: In a 13-week inhalation study all mice exposed at 800 ppm died and the respiratory tract lesions at 200 ppm and above were considered potentially life threatening. Therefore, exposure concentrations selected for mice for the 2-year studies were 50 and 100 ppm 1,2-epoxybutane.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Individual animal weights were recorded on the first day of treatment, weekly thereafter and at necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE: No

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

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, gallbladder, 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.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Female mice at 100 ppm were inactive and listless during the last 2 months on study; no other dose-related clinical signs were observed in either males or females.

Mortality:

mortality observed, treatment-related

Description (incidence):

The survival of the high dose female group was significantly lower than that of the controls after week 69. The survival of the high dose groups of males (P=0.002) and females (P=0.001) was significantly lower than that of the low dose groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of high dose male mice were generally higher than those of the controls until week 47 and 10%-14% lower after week 69. Mean body weights of low dose male mice were generally higher than those of the controls until week 69 and 4%-8% lower after week 86. Mean body weights of high dose female mice were 13%-23% lower than those of the controls after week 60. Mean body weights of low dose female mice were 12%-16% lower than those of the controls after week 73.

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

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nasal Cavity, Nasal Gland, Nasolacrimal Duct, and Olfactory Sensory Epithelium: Emphysema and chronic inflammation were diagnosed by the study pathologist to describe the presence of suppurative exudate in the nasal cavity and infiltration of the nasal mucosa with lymphocytes and macrophages. Erosion, respiratory epithelial regeneration and hyperplasia, and squamous metaplasia were observed at increased incidences in dosed male and dosed female mice. Cysts and hyperplasia of the nasal gland (Bowman's glands in the respiratory mucosa), suppurative and chronic inflammation and epithelial hyperplasia of the nasolacrimal duct, and atrophy of the olfactory sensory epithelium were also observed at increased incidences in dosed mice. A single squamous cell papilloma was seen in the incisive duct of one high dose male mouse.
Ovary or Uterus: Suppurative inflammation (primarily ovarian abscesses) of the uterus and/or ovary was present in all dosed groups (uterus: vehicle control, 6/50; low dose, 11/49; high dose, 7/48; ovary: 7/49; 20/47; 21/45). These lesions were cultured from one control, four low dose, and four high dose animals. Klebsiella oxytoca was isolated from each lesion.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Pituitary Gland: Adenomas or carcinomas (combined) in female mice occurred with a significant negative trend (P=0.018 by the incidental tumour test; control, 22/47; low dose, 12/46; high dose, 5/46).

Key result

Dose descriptor:

NOAEC

Remarks:

carcinogenicity

Effect level:

100 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no significant increase in neoplastic lesions compared to ctr

Key result

Critical effects observed:

no

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1981-11-25 to 1982-11-18

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

A 2-year inhalation exposure study was performed according to internal NTP guidelines.

GLP compliance:

yes

Remarks:

testing lab.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 7-8 weeks
- Weight at study initiation: ca. 191 g (males), ca. 137 g (females)
- Housing: housed individually in Hazleton chambers
- Diet: ad libitum, Feed was available ad libitum during non-exposure periods. NIH 07 Rat and Mouse Ration (Zeigler Bros., Gardners, PA)
- Water: ad libitum
- Acclimation period: 21 days

DETAILS OF FOOD AND WATER QUALITY: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 73-80°F
- Humidity (%): 40-76 (during exposure), ca. 43 during non-exposure
- Air changes (per hr): 10 during exposure/20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: room air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The liquid to be vaporized was contained in a 1.6-liter stainless steel reservoir housed in a vapor hood in the exposure room. The liquid was pumped from this reservoir to a stainless steel cylinder covered with a glass fiber wick from which the liquid was vaporized. An 80-watt heater and a temperature-sensing element were incorporated within the cylinder. The heater maintained the vaporizer at approximately 58°C. The surface temperature of the vaporizer was slightly lower. To minimize material loss due to condensation on duct walls, each cylindrical vaporizer was positioned in the fresh air duct leading directly into the exposure chamber.
Uniformity of vapor concentration in each exposure chamber was measured with a portable photoionization detector periodically throughout the studies. The data showed that when expressed as a percentage of the normalized average concentration of all 12 sampling positions, the standard deviation did not exceed 5% for all but two measurements. (For those two measurements, the standard deviation was within 10%.)
Samples of the atmosphere in the 1,2-epoxybutane exposure chamber were examined for the occurrence of potential degradation products, specifically 1,2-butandiol. Through the use of a Hewlett Packard model 5840A gas chromatograph equipped with a flame ionization detector and a 6 ft x 4 mm 1D glass column packed with 10% Carbowax 20M on 801100 Chromosorb WAW, a single homogeneous peak was observed; no evidence for any degradation was detected. It is concluded from this study that the 1,2-epoxybutane vapor generated during these studies was at least 99% pure.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

no

Dose / conc.:

200 ppm (nominal)

Remarks:

0.598 mg/L (nominal)

Dose / conc.:

400 ppm (nominal)

Remarks:

1.197 mg/L (nominal)

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Because of the lower body weight gain and nasal cavity inflammation at 800 ppm in a 13-weeks inhalation exposure study, 1,2-epoxybutane concentrations selected for rats for the 2-year studies were 200 and 400 ppm.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
All animals were observed two times per day, and clinical signs were recorded once per month.

BODY WEIGHT: Yes
- Time schedule for examinations: 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.

FOOD CONSUMPTION AND COMPOUND INTAKE: No

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No compound-related clinical signs were observed in either males or females.

Mortality:

mortality observed, treatment-related

Description (incidence):

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. Survival of rats was at least 50% in all groups until week 98, but survival was reduced after
this time in exposed groups (final survival male: control, 30/50; low dose, 18/50; high dose, 23/50; females: 32/50; 21/50; 22/50).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

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.

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

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nasal cavity: The incidence of papillary adenomas in high dose male rats was significantly greater than that in the controls. These tumours were exophytic papillary growths of a cuboidal to columnar non-ciliated 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 leukaemia 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 tumour test (the more appropriate test for analysis of these nonfatal tumours); 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 significant 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 tumour test (the latter test is considered more appropriate for analysis of nonfatal tumours).
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 tumour trend test (the more appropriate test for analysis of these non-fatal tumours). The incidence in the high dose group was not significantly greater than that in the controls.

Key result

Dose descriptor:

NOAEC

Remarks:

carcinogenicity

Effect level:

200 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no significant increase in neoplastic lesions compared to ctr

Key result

Dose descriptor:

LOAEC

Remarks:

carcinogenicity

Effect level:

400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

400 ppm

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Table 1: 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.

The finding of benign neoplasms of the nasal cavity (nasal cavity neoplasms have not been seen in any of the 249 chamber control male rats at this laboratory and in only 0.1% [2/1,977] of untreated control male rats in all NTP studies) and of benign and malignant neoplasms of the lung in male rats is clear evidence that this chemical is a carcinogen. The presence in female rats of two tumours in the nasal cavity, a site for tumours in male rats, is considered equivocal evidence of carcinogenicity.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

200 ppm

Study duration:

chronic

Species:

rat

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The substance is harmonized classified for carcinogenicity Cat.2 (H351) according to Annex VI of Regulation (EC) No 1272/2008.

Additional information

A study on carcinogenicity using male and female rats is available for the substance. Fischer 334 rats have been exposed to test item vapour concentrations (whole body) of 200 and 400 ppm. The study duration was 103 weeks and the frequency of treatment was 6 hours per day for 5 days per week. Control animals have been exposed to room air only. 50 animals per sex per dose were used for each group. The doses for the carcinogenicity study have been selected based on the results of a 13-week inhalation study. Because of the lower body weight gain and nasal cavity inflammation at 800 ppm in this 13-weeks inhalation exposure study, 1,2-epoxybutane concentrations selected for rats for the 2-year studies were 200 and 400 ppm. Survival of rats was at least 50% in all groups until week 98, but survival was reduced after this time in exposed groups (final survival- male: control, 30/50; low dose, 18/50; high dose, 23/50; female: 32/50; 21/50; 22/50). Mean body weights of high dose male rats were 5%-8% lower than those of controls after week 86, and mean body weights of high dose female rats were 5%-10% lower after week 22. With respect to the benign nasal tumours observed in this study, these showed no sign of progression to malignancy and must be seen against the background of extensive non-neoplastic lesions at this dose level (400 ppm). These tumours are likely to be a direct consequence of the irritant properties of 1,2-epoxybutane leading to stimulation of cell proliferation. It is, therefore, highly unlikely that these tumours occur at dose levels which do not produce chronic tissue irritation. A small but statistically significant incidence of lung tumours (carcinomas and adenomas combined) was confined to the male rat and to the top dose level of 400 ppm. These tumours occurred late in the study and showed no evidence of metastasis. The increase in malignant lung tumours alone was not statistically significant. It required the combination of benign and malignant tumours to obtain the statistical significance to enable the study authors to classify 1,2-epoxybutane as "clear evidence of carcinogenic activity". Furthermore, one could question whether a practical maximum Tolerated Dose was exceeded in the study in view of the significant upper respiratory tract irritation. The authors categorized the results obtained with female rats as "equivocal evidence of carcinogenic activity", demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be chemically related. Two high dose (400 ppm) females developed benign nasal cavity tumours and one female developed a benign alveolar/bronchiolar tumour. On the other hand, one female control developed a malignant alveolar/bronciolar tumour. On this basis it is highly questionable as to whether or not the treated females could be considered to "show a marginal increase of neoplasms that may be chemically related". The NOAEC for carcinogenicity from this study was 200 ppm (NTP, 1988).

In a further study, B6C3F1 mice have been exposed to test item vapour concentrations (whole body) of 50 and 100 ppm. The study duration was 102 weeks and the frequency of treatment was 6 hours per day for 5 days per week. Control animals have been exposed to room air only. 50 animals per sex per dose were used for each group. The doses for the carcinogenicity study have been selected based on the results of a 13-week inhalation study. Here, all mice exposed to 800 ppm died and the respiratory tract lesions at 200 ppm and above were considered potentially life threatening. Therefore, exposure concentrations selected for mice for the 2-year studies were 50 and 100 ppm 1,2-epoxybutane. Male and female mice did not show tumours in any organ at either dose level in this chronic inhalation vapour study (NTP, 1988).