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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:

Test animals

Details on test animals or test system and environmental conditions:
- Source: Hilltop Lab Animals, Inc. , Scottdale, PA
- Age at study initiation: 4-5 weeks (females), 8 weeks (males)
- Weight at study initiation: 100-125 g (females), 300-324 g (males)
- Fasting period before study:
- Housing: The animals were housed in stainless steel cages before, during, and after inhalation exposure. Caging of experimental females was individual within the exposure chamber except during the mating period. Cage assignment was not random and the locations were not rotated.
- Diet: Wayne Lab-Blox was provided ad libitum, except during the daily exposure period when the food was removed.
- Water: Water was supplied by an automatic watering system which was disconnected and drained prior to initiation of each exposure
- Acclimation period: ca 4 weeks

- Temperature (°C): no data
- Humidity (%): not controlled
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
other: room air
Details on exposure:
Rats were exposed in stainless steel chambers. A polydispersed particulate aerosol attained equilibirum in 15 - 20 min after introduction into the chamber. Concentrations measured above the six catch pans showed a 3 - 5% variation. The design of these chambers allows for up to 192 adult rats to be both exposed and housed within each chamber.
Three chambers were employed: one for the high-level, one for the low-level, and one for the pregestational filtered air exposure of rats. The same chambers were used for gestational exposure of rats. Animals were transferred to washed and sterilized chamber-caging units at least once a week.
HPE filtered air was continually suppled to the exposure chambers and the vapours under study were introduced into the filtered air streams. Chamber air flows were maintained at 10 cfm, which provided seven air changes per hour.
Methodology for generating the desired butylene oxide atmospheres was developed using an exposure chamber set up in the aerosol physic laboratory. Liquid butylene oxide was placed in a 3 -necked, 500 -ml distillation flask with a coarse fritted glass bubbler extending from the center neck into the liquid. One of the remaining necks was stoppered while the other had a tube extending into the inlet air line to the exposure chamber. Dry N2 gas was used at 0.225 -1.5 liters per minute to avoid explosive vapor concentrations in the generator. The liquid bath was heated to the temperatures necessary to generate the required amount of vapor. For the first three weeks of exposure, the butylene oxide was periodically replenished; subsequently it was replaced daily.
The generators were located in a fume hood, and connected to the exposure chambers by 3 -inch diameter flexible hose. The chamber was connected to a transvector air flow amplifier which introduced the exhaust air to another flexible hose which was connected to a room exhaust port. The total flow into the room exhaust hose was approx. 125 cfm of which only 10 cfm came from the chamber. To pump 10 cfm required about 3 cfm of drining air for a total output of 13 cfm. The system was adjusted to provide vapor concentrations in the chambers of 1000 and 250 ppm of butylene oxide.
Analytical verification of doses or concentrations:
gas chromatography
Details on analytical verification of doses or concentrations:
Concentrations within the chamber were uniform to within 10% and remained within this range over prolonged generation periods.
Details on mating procedure:
Pregestational exposures ordinarily began on a Monday and were continued for 7 hours per day, 5 days a week, for 3 weeks. The females were transferred to a standard rack united and caged with males (2:1). Vaginal lavages were performed the following mornings and examined for the presence of sperm. Sperm-positive females were randomly assigned to gestational exposure groups. Gestational exposures were started on the day on which sperm were detected which was denoted as day 1 of gestation (d.g. 1). Mating and initiation of gestational exposures continued for 7 - 9 days, until about 36 sperm-positive rats were assigned to each experimental group. Gestational exposures were performed 8 hours per day, 7 days per week, through d.g. 19. All exposed mated rats were sacrificed at d.g. 21.
Based upon the combination of pregestational and gestational exposures, 1 control and 6 experimental groups were formed. These groups will be identified by the pregestational and gestational exposure in the presentation of results:
Air-air (control) - 3-week pregestational exposure to filtered air followed by exposure to filtered air during days 1 - 19 of gestation. Air-low - 3-week pregestational exposure to filtered air followed by low level exposure during days 1-19 of gestation. Air-high - 3-week pregestational exposure to filtered air followed by high level exposure during days 1-19 of gestation. Low-air - 3-week pregestational low level exposure followed by exposure to
filtered air during days 1-19 of gestation. Low-low - 3-week pregestational low level exposure followed by low level exposure during days 1-19 of gestation. High-air - 3-week pregestational high level exposure followed by exposure to filtered air during days 1-19 of gestation. High-high - 3-week pregestational high level exposure followed by high level exposure during days 1-19 of gestation.
Duration of treatment / exposure:
day 1 - 19 of gestation, additionally groups with pregestational exposure of 21 days
Frequency of treatment:
7 hours/day, 5 days/week
Duration of test:
until day 21 (cesarian section)
Doses / concentrationsopen allclose all
Dose / conc.:
250 ppm (nominal)
0.75 mg/mL (nominal conc.)
Dose / conc.:
1 000 ppm (nominal)
3.0 mg/mL (nominal conc.)
No. of animals per sex per dose:
total: 380
Control animals:


Maternal examinations:

- Time schedule for examinations: The female rats were weighted at least twice weekly during pregestation exposure and on days 1, 7, 14 and 21 of gestation.



The animals were sacrificed by introduction of carbon dioxide into an euthanisa chamber. Necropsy were performed on all animals; liver, lung, and kidneys were weighed. Internal abnormalities of the pregnant and non-pregnant animals were also recorded. Samples of the ovaries, uterus, liver, lungs with trachea, and kidneys were perserved in 10% neutral buffered formalin. Histopathological examination was performed on tissues from 25% of the pregnant animals, selected at random. The residual tissues and the tissues from the remaining 75% of the animals and from the non-pregnant animals have been preserved for possible future examination.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early/late resorptions: Yes
Blood sampling:
not specified
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [all per litter ]
- Head examinations: Yes: [half per litter]
- Anogenital distance of all live rodent pups: no
Fisher's Exact Probability Test was used on the maternal and fetal data; Bonferronni's method was used to adjust for the problem associated with multiple comparisons against a control group. In all instances, differences from the control group at probability levels of 0.05 or less were accepted as statistically significant.
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
mortality observed, non-treatment-related
Description (incidence):
No mortality without pregestational exposure (0/38). High pregestational exposure caused one death (1/42). However, this death was not regarded as substance-related (the surviving animals showed no signs of severe toxicity; no further details are given in the report).
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Pregestational exposure to 1000 ppm of butylene oxide produced a slight, but statistically significant, reduction in the body weight of the rats relative to the controls at most time periods. The differences were transient and were not statistically significant at the end of the pregestation exposure. By 7 days of gestational exposure, the rats exposed at the high levels were significantly lighter than the controls, and remained lighter throughout the study.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No remarkable changes in food consumption were produced by pregestational or gestational exposure of rats.
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 specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The relative organ weight of liver, kidney and lung were not significantly changed compared to control. No statistically significant differences in placental weight were detected.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Lung: A variety of pulmonary lesions, generally classified as inflammations, were frequently seen in the rats. In nine rats there were focal alveolar inflammations (accumulations of lymphocytes and plasma cells) which were not directly associated with arterioles or bronchioles, and small granulomas were observed in 2 rats. Other changes in the lungs were seen in all experiments, but did not appear to be related to exposure. These include alveolar histiocytosis, a focal accumulation of large histiocytes in alveoli. Most rats showed slight mononuclear peribronchiolitis and perivasculitis-lymphoid nodules and plasma cells around the bronchioles and associated arterioles. These lesions are common for rats, and may reflect previous exposure to pathogenic organisms.
Kidney: Several rats of each dose group were considered to have interstitial nephritis. This diagnosis was used when any lymphocytes or plasma cells were seen in the interstitial tissues. These infiltrates were very minimal and considered normal. Evidence of glomerulonephrosis was not detected.
Uterus: Slight to mild mononuclear endometritis, i.e. any infiltrate of lymphocytes and/or plasma cells in the endometrium, was a consistent observation. These changes were, for the most part, considered within the normal range, particularly since all rats were pregnant. Apparently normal corpora lutea were noted in the sections of ovary from each rat.
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Total litter losses by resorption:
effects observed, non-treatment-related
Early or late resorptions:
effects observed, non-treatment-related
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
The exposure led to a slightly reduced percentage of sperm-positive rats which were pregnant (36/37, 33/37, 28/35, 33/42, 38/44, 33/40, 31/39 for air-air, air-low, air-high, low air, low-low, high-air and high-high respectively) although no clear dose relationship was seen and the decrease was not statistically significant.

Effect levels (maternal animals)

Key result
Dose descriptor:
Effect level:
1 000 ppm
Based on:
test mat.
Basis for effect level:
other: No adverse effect observed up to highest dose.

Maternal abnormalities

Key result
effects observed, non-treatment-related

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, non-treatment-related
Description (incidence and severity):
The exposure had no statistically significant effect on either the weight or length of the fetuses in rats.
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
effects observed, non-treatment-related
External malformations:
effects observed, non-treatment-related
Skeletal malformations:
effects observed, non-treatment-related
Visceral malformations:
effects observed, non-treatment-related

Effect levels (fetuses)

Key result
Dose descriptor:
Effect level:
> 1 000 ppm
Based on:
test mat.
Basis for effect level:
other: No teratogenicity observed up to highest dose tested.

Fetal abnormalities

Key result
effects observed, non-treatment-related

Overall developmental toxicity

Key result
Developmental effects observed:

Applicant's summary and conclusion