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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, GLP certified, similar to current guidelines

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990
Reference Type:
other: US EPA TSCA 8(e) submission
Title:
Unnamed
Year:
1990
Report Date:
1990
Reference Type:
publication
Title:
Evaluation of the inhalation toxicity of diethylethanolamine (DEEA) in rats.
Author:
Hinz, JP et al.
Year:
1992
Bibliographic source:
Fundam. Appl. Toxicol. 18: 418-424

Materials and methods

Principles of method if other than guideline:
mentions conforming to U.S. EPA guidelines for particular parameters, but, the exact guideline was not specified.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): diethylaminoethanol
- Analytical purity: 99%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory
- Age at study initiation: appr. 10 weeks
- Housing: individually
- Diet: Purina Certified Rodent Chow 5002, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature and relative humidity were monitored regularly and according to the report were within the ranges specified in U.S. EPA guidelines.


Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal and actual exposure concentrations were determined daily. Actual exposure concentrations are reported, and were measured by GC analysis. Samples were obtained hourly. Samples were drawn from 5 points in a horizontal plane within each exposure chamber.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
5 days/week, 6 hours/day
Doses / concentrations
Remarks:
Doses / Concentrations:
0.053, 0.120 and 0.365 mg/l (53, 120 and 365 mg/m3; original values: 11, 25 and 76 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: 4 weeks

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
Food and water consumption was determined monthly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to exposure initiation and monthly during the study.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at both week 14 and after recovery
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: No data
- How many animals: all
- Parameters were examined: erythrocyte, leukocyte, reticulocyte, and platelet counts, hematocrit hemoglobin, mean corpuscular hemoglobin value and concentration, and mean corpuscular volume

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at both week 14 and after recovery
- Animals fasted: No data
- How many animals: all
- Parameters examined: alanine aminotransferase, albumin, aspartate aminotransferase, blood urea nitrogen, creatinine, sodium, potassium and chloride, y-glutamyl transferase, globulin, glucose, sorbitol dehydrogenase, total bilirubin, and protein


URINALYSIS: Yes
- Time schedule for collection of urine: over a 16-hr period prior to termination
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: volume, color, pH, turbidity, occult blood, osmolarity, sediment, glucose, ketones, protein, bilirubin, urobilinogen, and creatinine clearance


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Neurologic exams were preformed monthly using a modified "Irwin Screen" during the exposure period.
- Dose groups that were examined: no data
- Battery of functions tested: not specified


Sacrifice and pathology:
Full histological exams [nasal cavity/turbinates, adrenal glands, bone and bone marrow (sternum), brain, epididymes, eyes, heart, kidneys, larynx, liver, lung, cervical lymph node, gastrocnemius muscle, gonads, parathyroid, pituitary, spinal cord, spleen, thymus, thyroid, trachea, urinary bladder and uterus] were conducted in the high dose group and control, but in the low and middle dose groups only the nasal cavity/turbinates were evaluated. The examination of the nasal cavity/turbinates (4 sections) was conducted according to the method of Young (Fund. Appl. Toxicol., 1, 309-312, 1981).
Statistics:
Bartlett's test, ANOVA, Dunnett's, Kruskall-Wallis test and several other tests if applicable.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
No animals died as a result of exposure to DEAE. During exposure, dose-dependent transient signs of mild to moderate respiratory irritation (sneeze-like sounds or rales) were noted. They usually cleared within one hour after exposure. In the high dose group, some animals continued to exhibit these signs overnight. Nasal discharge was observed at the beginning of the study, but this subsided as the study progressed.

BODY WEIGHT AND WEIGHT GAIN
Through the first 7 weeks of exposure the high dose group had a slight, but statistically significant decrease in body weight gain as compared to controls. Subsequently the rate of growth paralleled the other groups, but the initial decrement was never regained. Mean body weights of the high dose groups never decreased more than about 7 % from the controls.

FOOD CONSUMPTION
no pattern of persistent treatment related differences was evidenced.

OPHTHALMOSCOPIC EXAMINATION
Corneal opacities were observed in control and DEAE-treated animals. DEAE exposure appeared accelerate the appearance of this lesion in the middle and high concentration groups. Aging F344 rats are genetically predisposed toward developing these corneal lesions. Prolonged exposure to an alkaline compound such as DEAE might have accelerated an underlying predisposition toward corneal dystrophy. Since the opacity was thought to be due to a calcium precipitate, this problem may have also been exacerbated by the high vitamin D diet which would increase calcium absorption.

HAEMATOLOGY
hematology evaluations exhibited no biologically significant exposure-related differences between exposed and control groups.

CLINICAL CHEMISTRY
serum chemistry evaluations exhibited no biologically significant exposure-related differences between exposed and control groups.

URINALYSIS
urinanalysis exhibited no biologically significant exposure-related differences between exposed and control groups.
NEUROBEHAVIOUR
no pattern of persistent treatment related differences was evidenced.

ORGAN WEIGHTS
At week 14 there was a slight, but statistically significant increase in the absolute male liver and kidney weights in the high dose group (8.0 and 7.1 %, respectively), as well as in their relative weights (increased by 5.9 and 7.1 %, respectively), but histological changes were not associated with these findings.

GROSS PATHOLOGY
no pattern of exposure related macroscopic findings was evidenced.

HISTOPATHOLOGY: NON-NEOPLASTIC
The low dose group was free of exposure-related histological changes in the nasal cavities and turbinates, but changes were noted in the middle and high dose groups sacrificed in the 14th week of exposure. These consisted of an increased incidence [45 % (50 % M, 40 % F) at the middle concentration and 95 % (90 % M, 100 % F) at the high concentration] and severity of focal hyperplasias alone or in association with squamous metaplasia of the respiratory epithelium, and multi-focal mixed infiltrations of inflammatory cells in the nasal mucosa. Changes were most evident in the anterior sections of the nasoturbinates and on the lateral wall of the nasal cavity. In the high dose group hypertrophic goblet cells were seen in the nasal septum, along with a low incidence of focal necrosis and exudate in the lumen of the nasal cavity. The findings in the middle and high dose groups after the 4 week recovery period were similar to those seen in the 14 week rats, however, the incidence of focal hyperplasia with squamous metaplasia was decreased. The incidence of focal hyperplasia alone, infiltrations of inflammatory cells and goblet cell hypertrophy were comparable to what was noted at14 weeks. There were no exposure-related findings in the other areas of the respiratory system to indicate any irritating effect on the lower respiratory tract.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.365 other: mg/l
Sex:
male/female
Basis for effect level:
other: no systemic toxicological effects were  observed
Dose descriptor:
NOAEC
Effect level:
0.053 other: mg/l
Sex:
male/female
Basis for effect level:
other: Local effects
Dose descriptor:
LOAEC
Effect level:
0.12 mg/L air
Sex:
male/female
Basis for effect level:
other: Local effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

This study indicated that DEAE lacked systemic toxic properties, and the point of contact (eyes and upper respiratory tract) was the site of action. Since no systemic toxicological effects were observed, the NO[A]EC for systemic toxicity was the highest dose tested, i.e. 0.365 mg/l (76 ppm, or 365 mg/m³). The NO[A]EC for local toxicity, based on the lack of observed effects in the nasal cavity/turbinates, was 0.053 mg/l (11 ppm, rounded off to 10 ppm, or 53 mg/m³). The noises or rales at this concentration were considered an adaptive effect, but not an adverse effect, since no histological changes were observed at this concentration. However, since an effect (rales) was seen at the lowest concentration, a NOEC was not reached.


NO[A]EC, rat (inhalation)14 weeks, systemic toxicity: 0.365 mg/l (76 ppm or 365 mg/m³)
NO[A]EC, rat (inhalation) 14 weeks, local toxicity: 0.053 mg/l (10 ppm or 53 mg/m³)
LO[A]EC, rat (inhalation) 14 weeks, local toxicity: 0.12 mg/l (25 ppm or 120 mg/m³).

The average analytical concentrations were 10.5, 25.5 and 76 ppm. These concentrations are comparable to ca. 13, 29 and 88 mg/kg bw per day doses assuming 100 % lung deposition and absorption.

  

 

Applicant's summary and conclusion