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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1979-09-24 to 1984-05-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD 413
Principles of method if other than guideline:
In a subchronic inhalation toxicity study similar to OECD 413, tert-Butyl glycidyl ether was administered to 10 Fischer 344 rats/sex/concentration by whole body exposure at concentrations of 0, 25, 75 and 225 ppm (0, 0.13, 0.40 and 1.19 mg/L) for 6 hours per day/5 days per week during a 13 week-period. Effects on reproductive organs were assessed.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(tert-butoxymethyl)oxirane
EC Number:
231-640-0
EC Name:
(tert-butoxymethyl)oxirane
Cas Number:
7665-72-7
Molecular formula:
C7H14O2
IUPAC Name:
2-[(tert-butoxy)methyl]oxirane
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot 08239, obtained from The Dow Chemical Company production facilities at Freeport, TX.
- Expiration date of the lot/batch:
- Purity: >99% (indicated by gas chromatography at the beginning of the study, during the study and after the exposure.

Test animals

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, Inc., Portage
- Age at study initiation: 6-8 weeks
- Housing: The animals were housed singly in stainless steel cages with wire-mesh bottoms in rooms
- Diet (e.g. ad libitum): A standard laboratory diet (Purina Laboratory Chow, Ralston Purina Co., St. Louis, M0) was offered ad libitum except during exposure.
- Acclimation period: The animals were acclimated at laboratory conditions for approximately 3 weeks prior to initiating exposures.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 21 °C
- Humidity (%): approx. 50%
- Photoperiod (hrs dark / hrs light): 12 /12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
Target tBGE exposure concentrations of 25, 75 and 225 ppm were generated using the J-tube method described by Miller et al (1980).
Details on mating procedure:
n.a.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chambers:
The exposures were conducted in custom-built, stainless steel 4.3 m3 chambers with pyramidal-shaped ceilings and flat floors. Small (12") windows in the doors of the chambers allowed limited visualization of animals inside. The chamber design facilitated the use of rodent housing racks and cages for exposures; rabbits were transferred to wire mesh cages for each exposure. The chambers were operated under dynamic airflow conditions at a slight negative pressure relative to the surrounding area. Airflow through the chambers was maintained at approximately 800 lpm. Temperature and relative humidity in the chambers was recorded each day while exposures were in progress. Control animals were placed in a chamber of similar design (4.1 m3 Rochester-type) during the times exposures were in progress; the control chamber was supplied with clean, filtered air.

Vapor generation:
The nominal concentration (ratio of the amount of tBGE vaporized to the total amount of airflow through the chamber) was calculated for each chamber on a daily basis. The analytical concentration of tBGE in each chamber was measured approximately once each hour by gas chromatography using a Varian 2400 gas chromatograph with flame ionization detector. The operating conditions of the gas chromatograph were as follows:
Column: 6' x 1/8” stainless steel with UCW-98
(80/100 mesh on Chrom W-HP)
Column Temp: Isothermal 125 °C
Carrier: Nitrogen (50 mL/min)
Standards of known concentration were prepared by vaporizing measured amounts of tBGE in 100 liter Saran bags filled with a measured volume of filtered, dry air. Standardization of the analytical equipment was checked each exposure day with at least one standard of known concentration.
Duration of treatment / exposure:
64 days during a 13-week period
Frequency of treatment:
6 hours per day/ 5 days per week
Details on study schedule:
n.a.
Doses / concentrationsopen allclose all
Dose / conc.:
25 ppm (nominal)
Dose / conc.:
75 ppm (nominal)
Dose / conc.:
225 ppm (nominal)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Dose selection rationale: Prior to initiating this subchronic study, a 2-week vapor inhalation study was conducted in which rats were exposed to 0, 100, 300 or 1000 ppm tBGE 6 hours per day, 5 days per week, for a total of 10 days during a 14-day interval (Gushow et al., 1984). The rats which survived the exposure to 1000 ppm were extremely debilitated and in very poor nutritional condition as reflected by a severe depression in body weight gain, with concomitant changes in organ weights, clinical chemistries, and hematology. The body weights of rats in the 300 ppm group were significantly lower than controls. There was no apparent adverse effect on body weights of mice exposed to 300 ppm. Organ weights, clinical chemistries, urinalyses and hematology analyses for animals in the 300 ppm group gave no indication of a specific target organ; however, clinical signs in the higher exposure group suggest upper respiratory tract irritation. No adverse effects were found in animals in the 100 ppm group.
- Animals were equally divided by sex and randomly assigned to control or exposure groups using a computer-assisted randomization procedure.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: each day after exposure
All animals were observed after each day of exposure for signs of toxicity and changes in appearance and demeanor
BODY WEIGHT: Yes
- Time schedule for examinations: Immediately prior to the first exposure and weekly thereafter. Final body weights were recorded immediately prior to sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples from rats were taken by orbital sinus puncture after approximately 12 weeks of exposure
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked: Packed cell volume (PCV), hemoglobin concentration (Hgb), erythrocyte
count (RBC), leukocyte count (NBC), differential leukocyte count and red cell indices

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples for these determinations were taken from anesthetized animals at the time of necropsy
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked: Blood urea nitrogen (BUN), glutamic-pyruvic transaminase activity
(SGPT), alkaline phosphatase activity (AP), and glucose
Blood samples for these determinations were taken from anesthetized animals at the time of necropsy; blood was collected from severed cervical vessels.

URINALYSIS: Yes
- Time schedule for collection of urine: 1 week prior to scheduled necropsy, at the same time blood was collected for hematology analyses
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked: Specific gravity (refractive index), bilirubin, glucose, ketones, occult blood, pH, protein and urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No

GROSS PATHOLOGY: Yes (see table 1 in “Any other information on materials and methods”)
HISTOPATHOLOGY: Yes (see table 2 in “Any other information on materials and methods”)


Oestrous cyclicity (parental animals):
n.a.
Sperm parameters (parental animals):
n.a.
Litter observations:
n.a.
Postmortem examinations (parental animals):
n.a.
Postmortem examinations (offspring):
n.a.
Statistics:
Body weights, organ weights, hematology data, clinical chemistry data and urinary specific gravity were evaluated by analysis of variance and Dunnett‘s test (Steel and Torrie, 1960). Variances of group mean body weights were analyzed by Bartlett's test (Snedecor and Cochran, 1967). The nominal alpha level used was a = 0.05 in each case. Because numerous measurements on the same set of animals were statistically compared, the frequency of false positive (Type I) errors may have been much greater than the nominal alpha level.
Reproductive indices:
n.a.
Offspring viability indices:
n.a.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
All animals appeared normal throughout the course of the study.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights of male and female rats and mice in the 225 ppm group were significantly lower than controls as a result of exposure to the test material. The decreases in body weights were evident after approximately 2 to 3 weeks of exposure to 225 ppm; after 13 weeks, the mean body weights of male and female rats in the 225 ppm group were approximately 10% lower than for controls. Slight reductions in mean body weights of equivocal significance also occurred for female rats in the 75 ppm group. However, there were no apparent adverse effects on body weights for rats exposed to 25 ppm tBGE.
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:
no effects observed
Description (incidence and severity):
Hematologic parameters of rats were not affected by exposure to tBGE vapors.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Clinical chemistry analyses were unremarkable, revealing no differences in treatment groups of rats which were diagnostic of an adverse effect on any organ or tissue.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalyses revealed no differences between control and treatment groups of male and female rats
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
In the rats the only primary treatment-related effect seen as a result of inhalation exposure to tBGE was irritation of the nasal turbinate mucosa. The irritation was characterized by a variable amount of thickening (hyperplasia) and/or flattening of the respiratory epithelium. Inflammatory changes with some hyperplasia of mucus secreting glands was also seen in this region of the turbinate mucosa. The olfactory epithelial lined region of the nasal turbinates was less affected. These changes were typical of those seen in response to an irritating material. At the 225 ppm exposure level these lesions involved primarily the most anterior portion of the nasal cavity lined by respiratory epithelium with generally less involvement of the posterior nasal cavity lined by the olfactory epithelium. At the 75 ppm exposure level there was a minimal treatment-related effect that was confined to the respiratory epithelial region of the nasal cavity. None of these primary treatment-related changes were found in any of the 4 sections of nasal turbinates from any rats exposed to 25 ppm tBGE vapor.
There were microscopic changes observed in other tissues in the rats which were considered secondary to decreased food intake or stress, including: variable staining or accentuated lobular pattern in the liver suggestive of decreased glycogen deposition, decreased cortical thymocytes and decreased thymic adipobe tissue, and decreased fat in the mesenteric or mediastinal region. The thymic changes were evident at only the highest exposure concentration and were interpreted to be secondary stress-related. The liver changes and the decreased fat suggest that the animals exposed to 225 ppm tBGE vapor, and to a lesser extent the 75 ppm group, may not have been eating as much as the control animals. Inflammatory changes were observed in the lacrimal glands of rats of both sexes at all dose levels and in controls. The changes were not related to treatment but were considered to be an iatrogenic lesion secondary to the collection of blood samples via posterior orbital sinus puncture during the study. No changes were observed in the trachea, larynx, or lungs of any rats as a result of exposure to tBGE vapor, even at the highest exposure concentration where nasal turbinate effects were readily detected. No other lesions were observed in any other organ systems which were considered primary and related to exposure. There were no primary treatment-related changes in any organ or tissue in rats exposed to 25 ppm tBGE.
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Details on results (P0)

No effects on the reproductive organs in mice, rats and rabbits exposed to t-BGE via inhalation were seen. Exposure of male and female rats to 225 ppm tBGE for 13 weeks results in decreased body weight gain and concomitant changes in organ weights. These decreases in body weight gain were presumably the result of decreased food intake, as indicated by the observation of decreased abdominal adipose tissue at necropsy, and histopathologic observations in the liver suggestive of decreased glycogen deposition. Hematology parameters and bone marrow histopathology indicated that they were not adversely affected by exposure to tBGE vapors. Clinical chemistries and urinalyses revealed no changes diagnostic of adverse treatment-related effects in any target organs. Histopathologic examinations revealed no primary treatment-related effects in any organ or tissue except the nasal mucosa. The changes in the nasal mucosa were typical of those seen in response to an irritant -material, and were characterized in rats by a variable amount of epithelial thickening (hyperplasia) and inflammatory changes associated with some hyperplasia of mucus secreting glands. The changes in rats exposed to 225 ppm involved primarily the respiratory epithelial-lined regions of the nasal mucosa in the anterior portion of the nostril; the more posterior regions of the turbinate mucosa lined by olfactory epithelium were affected to a lesser degree. Minimal treatment-related effects were observed only in the respiratory epithelium in most of the animals exposed to 75 ppm. There were no treatment-related changes in any organ or tissue of rats exposed to 25 ppm.

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
225 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects seen on reproductive organs

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
tert-Butyl glycidyl ether elicits local effects in the nose at concentrations of 75 ppm. Systemic effects as body weight changes, decrease ot thymus weight and a decreased amount of adipose tissue were observed at the highest dose (225 ppm). Therefore a NOAEC (local) of 25 ppm and a NOAEC (systemic) of 75 ppm has been determined. This study was also conducted with mice and rabbits . Similar effects observed in the rat have been also seen in mice as well as in rabbits. No effects were seen on reproductive organs in female and male animals of all species tested.
Executive summary:

In a subchronic inhalation toxicity study similar to OECD 413, tert-Butyl glycidyl ether was administered to 10 Fischer 344 rats/sex/concentration by whole body exposure at concentrations of 0, 25, 75 and 225 ppm (0, 0.13, 0.40 and 1.19 mg/L) for 6 hours per day/5 days per week during a 13 week-period. Exposure of male and female rats to 225 ppm results in decreased body weight gain and concomitant changes in organ weights. Haematology parameters and bone marrow histopathology indicated that they were not adversely affected. Clinical chemistries and urinalyses revealed no changes diagnostic of adverse treatment-related effects in any target organs. Histopathologic examinations revealed no primary treatment-related effects in any organ or tissue except the nasal mucosa. The changes in rats exposed to 225 ppm involved primarily the respiratory epithelial-lined regions of the nasal mucosa in the anterior portion of the nostril; the more posterior regions of the turbinate mucosa lined by olfactory epithelium were affected to a lesser degree. Minimal treatment-related effects were observed only in the respiratory epithelium in most of the animals exposed to 75 ppm. There were no treatment-related changes in any organ or tissue of rats exposed to 25 ppm.

The NOAEC (local) is 25 ppm and NOAEC (systemic) is 75 ppm.

This study was also conducted with mice (10/group) and rabbits (4/group). Similar effects observed in the rat have been also seen in mice as well as in rabbits. No effects were seen on reproductive organs in female and male animals of all species tested.