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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 July 1991 to 5 September 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993
Reference Type:
publication
Title:
The inhalation toxicity of di- and triethanolamine upon repeated exposure.
Author:
Gamer AO, et al.
Year:
2008
Bibliographic source:
Food and Chemical Toxicology, 46(6), 2173-2183
Reference Type:
secondary source
Title:
Sub-acute Inhalation and Neurotoxicity of Triethanolamine (TEA)
Author:
Gamer AO, et al.
Year:
1998
Bibliographic source:
unpublished

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2,2',2''-nitrilotriethanol
EC Number:
203-049-8
EC Name:
2,2',2''-nitrilotriethanol
Cas Number:
102-71-6
Molecular formula:
C6H15NO3
IUPAC Name:
2,2',2''-nitrilotriethanol
Test material form:
liquid: viscous
Specific details on test material used for the study:
- Name of test material (as cited in study report): Triethanolamine; Substance No. 89/711
- Physical state: liquid/colourless
- Analytical purity: 98.9%
- Date of manufacture: June 29, 1989
- Lot/batch No.: Probe 912
- Stability under test conditions: ensured
- Storage condition of test material: under nitrogen

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: 7 weeks
- mean weight at study initiation: males: 239 g; females 168 g
- Fasting period before study: none
- Housing: individually
- Diet: KLIBA rat/mouse/hamster Iaboratory diet 24-343-4 10 mm pellets, KlingentalmuehIe AG, Kaiseraugst, Switzerland, ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF AN INHALATION ATMOSPHERE
- The test substance was supplied to a two-component atomizer by means of a continuous infusion pump and was atomized with compressed air. Having passed a glass separator, the liquid aerosol was diluted with conditioned blast air which was conducted via a glass bottle filled with bidist. water for humidification and was supplied to the exposure apparatus. In order to decrease the viscosity of the substance the two-component atomizers were warmed.
- The amounts of air which were set are listed in the table in ‘Any other information on materials and methods incl. tables’.

HEAD-NOSE EXPOSURE SYSTEM
- The head - nose exposure technique was preferably selected for this inhalation study to minimize fur contamination of the animals with the substance, which cannot be avoided during whole-body exposure. Fur contamination may lead to an additional dermal- and oral uptake (animals preen as their fur becomes contaminated). Thus an estimation of a nominal dose, taken up by the animals and its correlation to a toxic effect becomes more difficult.
- Furthermore, by using the dynamic mode of operation with a low-volume chamber, the equilibrium characteristic of this exposure technique is favourable: t99 (the time to reach 99% of the final target concentration) is shorter as compared with whole - body chambers with a higher chamber volume.
- The aerosol was generated inside an aerodynamic exposure apparatus (INA 20; volume V ~ 55 L, BASF Aktiengesellschaft). The apparatus consists of a cylindrical inhalation chamber of stainless steel sheeting and coneshaped outlets and inlets. The rats were restrained in exposure tubes (glass tubes), their snouts projected into the inhalation chamber and they thus inhaled the aerosol. The apparatus was also connected to an exhaust air system. The exhaust air system was set lower than the supply air system (positive pressure). This ensured that the aerosol in the breathing zones of the animals was not diluted by laboratory air.
- In order to accustom the animals to the exposure conditions they were exposed to supply air in head-only exposure systems under comparable flow conditions on 5 days before the exposure period (preflow period). The substance was administered as a liquid aerosol during a period of 28 days (20 exposures). All test groups were exposed for 6 hours on workdays. The number of exposures was 20. The animals did not have access to water or feed during the exposure.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days (20 exposures)
Frequency of treatment:
6 hrs/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0.02 mg/L air (analytical)
Dose / conc.:
0.1 mg/L air (analytical)
Dose / conc.:
0.5 mg/L air (analytical)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT DATA
The body weight of the animals was checked at the beginning of the preflow, one day before beginning of the exposure period and then once a week always at the same time of the day.

CLINICAL SIGNS AND FINDINGS
The behaviour and state of health of the test animals were checked on workdays at least 3 times on exposure days and one during the preflow period and the post observation days.

MORTALITY
A check for dead animals was made daily.

NEUROFUNCTIONAL TESTS
- The evaluation on neurofunction was performed on all animals before the beginning of exposure on study days 0, day 1, 8, 14, and 27 (last exposure).
- The examination was performed using a functional observational battery which includes various parameters of sensoric and motoric function as follows:
tremors, convulsions, piloerection, lacrimation, secretion of pigmented tears, salivation, pupil size, diarrhoea, vocalization, paresis, paralysis, ataxia, general appearance, body tone, posture, animal body (appearance), locomotor activity, respiration, urination, skin colour, righting reflex, behaviour, grip strength, pupillary reflex, winking reflex, vision, audition, olfaction, sensitivity of the body surface, pain perception (hot plate test), , tail pinch, toe pinch, visual placing response, miscellaneous.

CLINICAL CHEMISTRY AND HAEMATOLOGY
Blood was taken from the retroorbital venous plexus in the morning from non-fasted, not anesthetized animals. The blood samplings and the subsequent analysis of blood and serum was carried out in a randomized sequence. The assays were performed under internal lab quality conditions with commercial reference controls to assure reliable test results.
Sacrifice and pathology:
GROSS PATHOLOGY and HISTOPATHOLOGY: Yes
- At the end of the study 3 animals/sex and group were perfusion fixed for eventual further neuropathology which, however, was not performed because no neurotoxic findings were observed clinically and in routine histopathology of brain and sciatic nerve. The remaining 7 animals/sex and group were subjected to conventional necropsy. 7 animals per sex of the high concentration group and of the controls were subjected to histopathological examination, the scope of organs of OECD 412 being extended by brain and peripheral nerve.
Statistics:
- Means and standard deviation
- Statistical relevance was established using methods of ANOVA and DUNNETT
- KRUSKALWALLIS test
- MANN-WHITNEY U test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During the whole study period the animals of test groups 0 to 2 showed no abnormal clinical signs and findings. Reddish crusts on nasal edges (blood test positive) were detected in the animals of test group 3 after exposure during the second half of exposure period (males on days 21 to 23, 26 and 27, females on days 14 to 16, 20 to 23, 26 and 27).
Mortality:
no mortality observed
Description (incidence):
No deaths were recorded throughout the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight change of male and female animals from all test groups showed no statistically significant difference when compared to the control group.
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):
No substance-induced changes were observed in the hematological parameters or in clotting analysis of both sexes.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No substance-induced changes were observed in the enzyme activities or the blood chemistry parameters of both sexes.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
The statistically significant increased grip strength of forelimbs in males of test group 2 on day 14 and decreased grip strength of hind limbs in females of test group 3 on day 1 were judged to be not substance related because there was no concentration or time dependence. All other parameters examined during neurofunctional testing did not show any difference between animals exposed to the test substance and controls. Therefore functional observational battery did not reveal any substance-induced neurofunctional impairment in the treated groups when compared to control.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Local effects were characterized histopathologically by focal inflammatory changes in the submucosa of the larynx region, which seems to be the most sensitive part of the respiratory tract after aerosol exposure to the test substance. There was a tendency to concentration dependent increase in incidence and severity of the lesion from mid to high concentration in both sexes. The effect was found in females to a lesser extent. In this sex 0.02 mg/L did not cause larynx irritation anymore. In male animals however minimal to slight effects were observed in the low concentration similar to the mid concentration. Because of this similar grade of the lesion it is concluded that just below 0.02 mg/L no irritation should be present anymore.
Histopathological findings: neoplastic:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
There is a statistically significant inter-group difference between the red blood cells of the male animals of the control and those of test group 2. This deviation is marginal, inconsistent, when compared with the other sex, and lacking dosage-relationship. Accordingly, this finding is considered to be of no toxicological significance. 

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
systemic effects
Effect level:
0.5 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects at highest concentration tested
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
0.02 mg/L air
Based on:
test mat.
Sex:
female
Basis for effect level:
other: irritation of the upper respiratory tract
Remarks on result:
other: converted to BMCL05 = 14.1mg/m3
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
0.02 mg/L air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: irritation of the upper respiratory tract, minimal to moderate focal inflammatory change in the submucosa of the larynx
Remarks on result:
other: converted to BMCL05 = 14.8mg/m3

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion