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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]

4. DATA MATRIX
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]

4. DATA MATRIX
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
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
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: 7 weeks
- mean weight at study initiation: males: 239; 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
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The substance to be tested 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 following amounts of air were set:

Test group Compressed air [m³/h] Blast air [m³/h] Exhaused air [m³/h]
0 - 3.0 ± 0.3 2.7 ± 0.3
1 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3
2 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3
3 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3

Test group Substance flow atomizer [ml/h] Atomizer temperature [° C]
1 0.2 38.9 – 41.2
2 1.2 – 4.0 38.7 – 39.9
3 20 - 35 38.2 – 39.9

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 contaminited). 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 Iow-volume chamber, the equilibrium characteristic of this exposure technique is favorable: t99 (the time to reach 99% of the final target concentraiion) is shorter as compared with whole - body chambers with a higher chamber volume.

The aerosol was generated inside an aerodynamic exposure appalatus (INA 20; volume V ~ 55 I, 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) . Then alI test groups were exposed for 6 hours on workdays over a time period of 28 days (285 days test). 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
Frequency of treatment:
6 hrs/day, 5 days/week
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
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: one day before beginning of the exposure period and then once a week

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 3 times on exposure days and once during the post observation period.

BODY WEIGHT: Yes
- Time schedule for examinations: at D1 and at D27

HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning following last exposure
- Anaesthetic used for blood collection: No
- Animals fasted: No

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning following last exposure
- Animals fasted: Yes / No / Not specified
- How many animals: 5 animals / test group

URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: No
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: performed on all animals before the beginning of exposure on study days 0, day 1, 8, 14, and 27 (last exposure).
- Battery of functions tested: tremors, convulsions, piloerection, lacrimation, secretion of pigmented tears, salivation, pupil size, diarrhea, vocalization, paresis, paralysis, ataxia, general appearance, body tone, posture, animal body (appearance), locomotor activity, respiration, urination, skin color, righting reflex, behavior, grip strenght, pupillary reflex, winking reflex, vision, audition, olfaction, sensitivity of the body surface, pain perception (hot plate test), , tail pinch, toe pinch, visual placing response,
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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 alI 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 specified
Behaviour (functional findings):
effects observed, non-treatment-related
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
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 Triethanolamine. 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 ng/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 simiIar grade of the lesion it is concluded that just below 0.02 ng/l no irritation should be present anymore
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Key result
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 observed at the highest concentration tested
Key result
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
0.02 mg/L air
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
irritation of the upper respiratory tract
Key result
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
<= 0.02 mg/L air
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
focal inflammatory changes in the submucosa of the larynx
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.2 mg/L air
System:
respiratory system: upper respiratory tract
Organ:
larynx
Treatment related:
yes
Dose response relationship:
yes
Conclusions:
The LOAEC (local effects) was established to be 0.02 mg/litre (equivalent to23 mg/kg bw/day), based on the minimal to slight effects seen in the larynx of males.The NOAEC (systemic effects) was established to be0.5 mg/litre (equivalentto 575 mg/kg bw/day), based on the absence of effects at the highest dose tested.

In a sub-acute 28-day inhalation toxicity study (OECD 412),rats exposed to TEA for 6 hours/dayand 5 days/week displayed concentration-dependant focal inflammatory changes in the submucosaof the larynx. There were no systemic findings.
Executive summary:

In a sub-acute 28-day inhalation toxicity study (OECD 412), rats exposed to TEA for 6 hours/day and 5 days/week displayed concentration-dependant focal inflammatory changes in the submucosa of the larynx. There were no systemic findings.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
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
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:
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: 7 weeks
- mean weight at study initiation: males: 239; 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
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The substance to be tested 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 following amounts of air were set:

Test group Compressed air [m³/h] Blast air [m³/h] Exhaused air [m³/h]
0 - 3.0 ± 0.3 2.7 ± 0.3
1 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3
2 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3
3 1.5 ± 0.3 1.5 ± 0.3 2.7 ± 0.3

Test group Substance flow atomizer [ml/h] Atomizer temperature [° C]
1 0.2 38.9 – 41.2
2 1.2 – 4.0 38.7 – 39.9
3 20 - 35 38.2 – 39.9

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 contaminited). 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 Iow-volume chamber, the equilibrium characteristic of this exposure technique is favorable: t99 (the time to reach 99% of the final target concentraiion) is shorter as compared with whole - body chambers with a higher chamber volume.

The aerosol was generated inside an aerodynamic exposure appalatus (INA 20; volume V ~ 55 I, 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) . Then alI test groups were exposed for 6 hours on workdays over a time period of 28 days (285 days test). 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
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
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: one day before beginning of the exposure period and then once a week

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 3 times on exposure days and once during the post observation period.

BODY WEIGHT: Yes
- Time schedule for examinations: at D1 and at D27

HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning following last exposure
- Anaesthetic used for blood collection: No
- Animals fasted: No

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning following last exposure
- Animals fasted: Yes / No / Not specified
- How many animals: 5 animals / test group

URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: No
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: performed on all animals before the beginning of exposure on study days 0, day 1, 8, 14, and 27 (last exposure).
- Battery of functions tested: tremors, convulsions, piloerection, lacrimation, secretion of pigmented tears, salivation, pupil size, diarrhea, vocalization, paresis, paralysis, ataxia, general appearance, body tone, posture, animal body (appearance), locomotor activity, respiration, urination, skin color, righting reflex, behavior, grip strenght, pupillary reflex, winking reflex, vision, audition, olfaction, sensitivity of the body surface, pain perception (hot plate test), , tail pinch, toe pinch, visual placing response,
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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 alI 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 specified
Behaviour (functional findings):
effects observed, non-treatment-related
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
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 Triethanolamine. 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 ng/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 simiIar grade of the lesion it is concluded that just below 0.02 ng/l no irritation should be present anymore
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

open allclose all
Key result
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 observed at the highest concentration tested
Key result
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
0.02 mg/L air
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
irritation of the upper respiratory tract
Key result
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
<= 0.02 mg/L air
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
focal inflammatory changes in the submucosa of the larynx

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.2 mg/L air
System:
respiratory system: upper respiratory tract
Organ:
larynx
Treatment related:
yes
Dose response relationship:
yes

Applicant's summary and conclusion

Conclusions:
The LOAEC (local effects) was established to be 0.02 mg/litre (equivalent to23 mg/kg bw/day), based on the minimal to slight effects seen in the larynx of males.The NOAEC (systemic effects) was established to be0.5 mg/litre (equivalentto 575 mg/kg bw/day), based on the absence of effects at the highest dose tested.

In a sub-acute 28-day inhalation toxicity study (OECD 412),rats exposed to TEA for 6 hours/dayand 5 days/week displayed concentration-dependant focal inflammatory changes in the submucosaof the larynx. There were no systemic findings.
Executive summary:

In a sub-acute 28-day inhalation toxicity study (OECD 412), rats exposed to TEA for 6 hours/day and 5 days/week displayed concentration-dependant focal inflammatory changes in the submucosa of the larynx. There were no systemic findings.