Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptably documented study which meets basic scientific principles and contains sufficient detail to be able to judge the results reliable as a contribution to the understanding of the repeat dose toxicity of this substance.

Data source

Reference
Reference Type:
publication
Title:
Diethylene glycol monomethyl ether 13 week vapor inhalation toxicity study in rats
Author:
Miller RR, Eisenbrandt DL, Gushow TS, Weiss SK
Year:
1985
Bibliographic source:
Fund Appl Toxicol 7, 1174-9

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
, no opthalmology, clotting potential.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): diethylene glycol monomethyl ether
- Physical state: liquid
- Analytical purity: 99.5% (by gas chromatography at start and end of study.)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kingston, NY
- Age at study initiation: 6-8 weeks
- Weight at study initiation: Animals found to be statistical outliers based on weight were excluded.
- Fasting period before study:
- Housing: two per cage, stainless steel cages with wire floors.
- Diet (ad libitum except during exposure): Purina certified lab chow, Ralston Purina Co, St Louis, MO
- Water (ad libitum except during exposure): tap
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2C
- Humidity (%): 40-60%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester type 1m3 stainless steel and glass.
- Method of holding animals in test chamber: none specified
- Temperature, humidity, pressure in air chamber: as described in details of test animals. Target temperature 77F and humidity 50%
- Air flow rate: 90 litres/min (lower than usual to enable higher concentrations to be maintained.) Chambers operated under dynamic airflow conditions at a slight negative pressure.
- Method of vapour generation: Liquid test substance metered into a J tube assembly, vapours from which were swept into the chamber inlet ducts with compressed air (preheated to 60C) for further dilution with incoming air

TEST ATMOSPHERE
- Brief description of analytical method used: Nominal concentrations were calculated on a daily basis based on loss of test substance. Actual concentrations in test chambers were monitored every hour by gas chromatography. Chromatograph output was monitored by a strip chart recorder and simultaneously coupled to an electronic stream selector which calculated the mean daily exposures. Standards of known concentration were prepared by evaporating measured amounts of test substance into Teflon bags filled with known amounts of dry air. Calibration using at least one standard was performed daily and a full calibration curve using a number of standards obtained every 4 weeks.
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See details on inhalation exposure.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week (excluding public holidays, not specified.)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 30ppm, 100ppm, saturated vp (0, 150mg/m3, 100mg/m3, saturated vp). The theoretical saturated vapour concentration is 329ppm.
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
30.5+/-1.8, 101.5+/-3.9, 216+/-17ppm. Note that the top dose was the maximum practically attainable.
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale:
- Rationale for species selection: rats show toxic effects when exposed to the closely related glycol ether methoxyethanol.
- top dose was maximum concentration that could be achieved with this test substance under dynamic conditions (representing about 65% of the theoretical equilibrium saturated vapour concentration.)
- no satellite exposure groups.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: appearance and demeanor

BODY WEIGHT: Yes / No / No data
- Time schedule for examinations: at start and end of study and at weekly intervals in between.

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: end of study only.
- Dose groups that were examined: no data, assumed all dose groups.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 12 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: assumed all animals.
- Parameters checked: PCV, Hgb, RBC count, erythrocyte indices (MCV, MCH, MCHC, platelet count, total and differential leucocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 13 weeks
- Anaesthetic used for blood collection: No data
- How many animals: assumed all animals.
- Parameters checked: BUN, glucose, total protein, albumin and globulins. Activities of: glutamic-pyruvic transaminase , glutamic-oxaloacetic transaminase, alkaline phosphatase.

URINALYSIS: Yes
- Time schedule for collection of urine: 12 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: bilirubin, glucose, ketones, blood, pH, protein, urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. adrenals, aorta, bone and bone marrow, brain, cecum, cervix, coagulating gland, epididymis, esophagus, eyes, heart, intestines (small and large), kidneys, lachrimal/harderian gland, larynx, liver, lung, lymph node (mesenteric, mediastinal), mammary gland, mediastinal tissue, mesenteric tissue, nasal tissue, nerve (peripheral) ovaries and oviduct, pancreas, parathyroids, pituitary, prostate, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, stomach, salivary gland, testes, thyroid, thymus, tongue, trachea, urinary bladder, uterus, vagina, Zymbal gland.

Testes preserved in Bouin's solution, all other tissues from organs above in neutral phosphate buffered 10% formalin. Liver, kidneys, brain, heart, testes and thymus were weighed from all animals. Lungs were re-inflated with formalin and nasal cavities flushed to ensure rapid fixation of nasal mucosa.

HISTOPATHOLOGY: Yes. Complete sets of tissues from control and high exposure groups examined by embedding in parrafin, sectioning (5-6um) and examination after H&E staining by light microscopy

Statistics:
Evaluated by Barlett's test (p=.01) for the equality of variances: body weight, clinical chemistry, haematology (excluding red cell indices and differential WBC counts), urinary sg, organ weights, organ to body weight ratios. If group variances were homogeneous, parametric analysis of variance (p=0.1) was conducted to check for statistical difference between groups followed by Dunnett's test (p=.05) to check if overall analysis of variance was significant to check for statistical significance between experimental groups and respective controls. If group variances were heterogeneous, data was evaluated by non-parametric analysis of variance, and, if significant, Wilcoxon's rank sum test (p=0.05) with Bonferroni's correction. Statistical methods for determining outliers were also used.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN: Body weights of the mid dose females were lower than controls for the first 4 weeks. Since no effects were seen in the top dose animals, this observation was not attributed to the test material. No effects were seen in males.

Effect levels

Dose descriptor:
NOAEC
Effect level:
> 1 060 mg/m³ air
Sex:
male/female
Basis for effect level:
other: No effects seen at maximum concentration achievable.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Substantial condensation of test material was seen in the inlet ducts to the top dose test chamber. It is possible that there may have been some exposure to aerosol in the top dose group. The mean daily nominal concentration was 343ppm, with the difference between this and the analytical figure due to these condensation losses. Measured and nominal concentrations at the two lower doses were within 10% of each other.

Applicant's summary and conclusion

Conclusions:
It can be concluded that there is no hazard evident in rats from any conceivable exposure to vapour.
Executive summary:

In a sub-chronic inhalation toxicity study that closely followed the requirements of a guideline study, male and female rats were exposed to 2 -(2 -methoxyethoxy)ethanol at concentrations up to and included saturated vapour concentrations. No changes were seen in any of the measured parameters, including body weight, haematology, clinical chemistry, urinalysis and gross and histopathological organ examination that could be attributed to substance exposure. Based on this result, a NOAEC of 216ppm or 1060mg/m3 can be established and more importantly, it can be concluded that there is no hazard evident in rats from any conceivable exposure to vapour

Synopsis

NOAEC (inhalation, rats) >1060mg/m3 .