Registration Dossier

Administrative data

Description of key information

- Acute toxicity oral: similar to OECD 401, rats, dose levels: 190, 1900, 3100, 3900, 4850 and 6200 mg/kg bw. LD50 is ca. 4800 mg/kg bw(m/f);
- Acute toxicity inhalation: data waiving due to low vapour pressure and absence of mortality in acute inhalation tests with the source substance BEA (CAS 111-75-1) and DBEA (102-81-8);
- Acute toxicity dermal: GLP, OECD 402, Wistar rats, Dose level: 2000 mg/kg bw; no effects, slight skin reactions; LD50 > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to an acceptable BASF-test which in principle was similar to OECD 401; GLP was not compulsory at the time the study was conducted.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Observation period was 7 days in place of 14.
Principles of method if other than guideline:
The study was conducted according to an acceptable BASF-test which in principle was similar to OECD guideline 401.
Five male and five female rats per test group were administered following doses of test item: 200, 2000, 3200, 4000, 5000 and 6400 mg/kg bw; the dose level 3200 mg/kg bw was tested twice. The test item was administered by gavage (single application) as aqueous solution; the application volume depending on the test dose ranged from 10 to 21 mL/kg bw.
Following treatment, the animals were regularly examined for mortality and clinical signs of toxicity over an observation period of 7 days; body weights were recorded at test starting. All rats that died during the observation period as well as the surviving rats, which were sacrificed at the end of the observation period, were subjected to necropsy.
GLP compliance:
no
Remarks:
GLP was not compulsory at the time the study was conducted
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: US-Rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: young adult, no more data provided
- Weight at study initiation: males, 175 - 286 g; females, 150 - 210 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
other: water with Traganth
Details on oral exposure:
- Concentration in vehicle (%): 2%, 20% and 30%
- Amount of vehicle: from 10 to 21 mL/kg bw
Doses:
Original values as given in study report: 200, 2000, 3200, 4000, 5000 and 6400 mm3/kg bw
Values converted into mg/kg bw (density: 0.970 g/cm3): ca. 190, 1900, 3100, 3900, 4850 and 6200 mg/kg bw
No. of animals per sex per dose:
10 animals /sex/dose group (dose level 3100 mg/kg bw was repeated).
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- The animals were observed for mortality twice each workday and once daily at weekends or public holidays;
- They were regularly observed for clinical symptoms of toxicity after following treatment and once daily thereafter.
- Body weight was determined before the start of the study only and served for the determination of the dosage.
- At the end of the observation period, the surviving animals were sacrificed for the purpose of necropsy;
- Animals that died during the observations period also were subjected to necropsy.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 4 800 mg/kg bw
Based on:
test mat.
Remarks on result:
other: original value was given as 5000 mm3/kg bw
Mortality:
- At 190 mg/kg bw, none of the treated animals died.
- At 1900 mg/kg bw, none of the treated animals died.
- At 3100 mg/kg bw, in the first test, mortality was 30% (3/5 females died).
- At 3900 mg/kg bw, mortality was 10% (1/5 females died).
- At 4800 mg/kg bw, none of the treated animals died.
- At 6200 mg/kg bw, mortality reached 80% (4/5 males and 4/5 females).
- At 3100 mg/kg bw, in the second test, none of the treated animals died.

Almost all cases of death occurred within 48 hours following treatment.
Clinical signs:
- At the lowest dose levels of 190 and 1900 mg/kg bw, slight dyspnoea, prostration and piloerection were observed for 3 to 4 days following treatment; thereafter, the animals were free of symptoms.
- At a dose level of 3100 mg/kg bw, slight dyspnoea, prostration, piloerection, irregular breathing, unclean fur in the anal region and red incrusted noses were reported following treatment. The surviving animals recovered from day 3 post treatment.
- At the highest tested doses (3900, 4800 and 6200 mg/kg bw), irregular breathing, slight dyspnoea, agitation, slight salivation, high legged walking,and slight tremor when touched, were the main symptoms reported. Regarding the surviving animals, these showed partly incrusted eyes, piloerection, prostration and unclean fur; they recovered from day 5 to 6 post treatment.

Gross pathology:
Necropsy of some of the sacrificed animals revealed signs of bronchitis and bronchiectasis. In two cases, necropsy of animals that died revealed a poor nutritional status and diarrhea. No further abnormalities were noticed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 was determined to be ca. 4800 mg/kg bw, for both male and female rats.
CLP: not classified
DSD: not classified
Executive summary:

Butyldiethanolamine was tested for acute oral toxicity by gavage in rats according to a BASF internal method. The test method is considered to be scientifically acceptable since similar to the OECD TG 401. Five rats per sex and group were treated by single application at following dose levels: ca. 190, 1900, 3100, 3900, 4850 and 6200 mg/kg bw. For the 3100 mg/kg bw dose level, the initial test was repeated. The animals were observed over a period of 7 days for mortalities and clinical symptoms of toxicity. At the end of the observation period, those animals that had survived the experiment were sacrificed for the purpose of necropsy. Those animals that died during the experiment also were subjected to gross pathological examination.

At 190 and 1900 mg/kg bw, none of the treated animals died. At 3100 mg/kg bw, in the first test, mortality was 30 % (3/5 females died), while in the second test at the same dose level, none of the treated animals died. At 3900 mg/kg bwm mortality was 10 % (1/5 females died), while at 4800 mg/kg bw, again, none of the treated animals died. At 6200 mg/kg bw, mortality reached 80 % (4/5 males and 4/5 females). Almost all cases of death occurred within 48 hours following treatment. Among clinical signs, slight dyspnoea, prostration, piloerection, irregular breathing, unclean fur in the anal region and red incrusted noses were observed at the dose levels of 190, 1900 and 3100 mg/kg bw. The surviving animals recovered from day 3 post treatment.

At the highest tested doses (3900, 4800 and 6200 mg/kg bw), irregular breathing, slight dyspnoea, agitation, slight salivation, high legged walking, and slight tremor when touched, were the main symptoms reported. Regarding the surviving animals, these showed partly incrusted eyes, piloerection, prostration and unclean fur; they recovered from day 5 to 6 post treatment. Necropsy of some of the sacrificed animals revealed signs of bronchitis and bronchiectasis. In two cases, necropsy of animals that died revealed a poor nutritional status and diarrhea. No further abnormalities were noticed.

LD50 was determined to be ca. 4800 mg/kg bw, for both male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 800 mg/kg bw
Quality of whole database:
Acceptable well documented study which meets general scientific principles.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Acute hazard inhlation tests are available for the source substances Butylethanolamine (CAS 111-75-1) and Dibutylethanolamine (CAS 102-81-8).

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July-September 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP standards (Schedule 1, Good Laboratory Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994)).
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Wistar (RccHan:WIST) strain
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: at least 200 g (the weight variation did not exceed ±20% of the mean weight for each sex).
- Fasting period before study: no
- Housing: individually during the 24-Hour exposure period and in groups of five, by sex, for the remainder of the study
- Diet (e.g. ad libitum): ad libitum (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK)
- Water (e.g. ad libitum): ad libitum (mains drinking water)
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 07 August 2014 To: 21 August 2014
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: backs and flanks
- % coverage: 10
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated skin and surrounding hair were wiped with cotton wool moistened with distilled water to remove any residual test item.
- Time after start of exposure: 24 hours

TEST MATERIAL
For the purpose of the study the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.
- Amount(s) applied (volume or weight with unit): 2.08 (based on specific gravity of 0.966)
- Constant volume used: yes

Duration of exposure:
24 hours
Doses:
The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed: clinical signs, body weight

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No treatment related effects
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
- Other observations: dermal reactions.
Very slight erythema was noted at the test site of one male. Very slight erythema, small superficial scattered scabs and glossy skin were noted at the test sites of four females.
There were no signs of dermal irritation noted at the test sites of four males and one female.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.
The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Executive summary:

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths or signs of systemic toxicity. Very slight erythema was noted at the test sites of one male and four females. Small superficial scattered scabs and glossy skin were also noted at the test sites of four females. There were no signs of dermal irritation noted at the test sites of four males and one female. All animals showed expected gains in body weight. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
GLP guideline study

Additional information

Acute toxicity: oral

Butyldiethanolamine was tested for acute oral toxicity by gavage in rats according to a BASF internal method (BASF, 1967; Report No. XVII/49). The test method is considered to be scientifically acceptable since similar to the OECD TG 401. Five rats per sex and group were treated by single application at following dose levels: ca. 190, 1900, 3100, 3900, 4850 and 6200 mg/kg bw. For the 3100 mg/kg bw dose level, the initial test was repeated. The animals were observed over a period of 7 days for mortalities and clinical symptoms of toxicity. At the end of the observation period, those animals that had survived the experiment were sacrificed for the purpose of necropsy. Those animals that died during the experiment also were subjected to gross pathological examination.

At 190 and 1900 mg/kg bw, none of the treated animals died. At 3100 mg/kg bw, in the first test, mortality was 30 % (3/5 females died), while in the second test at the same dose level, none of the treated animals died. At 3900 mg/kg bw mortality was 10 % (1/5 females died), while at 4800 mg/kg bw, again, none of the treated animals died. At 6200 mg/kg bw, mortality reached 80 % (4/5 males and 4/5 females). Almost all cases of death occurred within 48 hours following treatment. Among clinical signs, slight dyspnoea, prostration, piloerection, irregular breathing, unclean fur in the anal region and red incrusted noses were observed at the dose levels of 190, 1900 and 3100 mg/kg bw. The surviving animals recovered from day 3 post treatment.

At the highest tested doses (3900, 4800 and 6200 mg/kg bw), irregular breathing, slight dyspnoea, agitation, slight salivation, high legged walking, and slight tremor when touched, were the main symptoms reported. Regarding the surviving animals, these showed partly incrusted eyes, piloerection, prostration and unclean fur; they recovered from day 5 to 6 post treatment. Necropsy of some of the sacrificed animals revealed signs of bronchitis and bronchiectasis. In two cases, necropsy of animals that died revealed a poor nutritional status and diarrhoea. No further abnormalities were noticed.

LD50 was determined to be ca. 4800 mg/kg bw, for both male and female rats.

Acute toxicity: inhalation

There is no reliable information available for acute toxicity by inhalation for Butyldiethanolamine. Therefore, the data on source substances Butylethanolamine (CAS 111 -75 -1) and Dibutylethanolamine (CAS 102 -81 -8) have been considered.

In an inhalation hazard test (IHT; BASF, 1977) conducted with Butylethanolamine (CAS 111 -75 -1), 3 rats per sex were exposed to a saturated vapour atmosphere of the test substance for 8 hours. The mean nominal concentration of the test substance was 24.69 mg/L. No animal died. Mucous membrane irritation was observed and no abnormalities were seen at necropsy.

Three inhalation hazard tests investigating inhalation toxicity of Dibutylethanolamine are available:

In the first inhalation hazard test (IHT) by BASF (No. XVII/143, 1967), 6 male and 6 female rats were exposed to a test atmosphere saturated with vapours of test substance for 8 hours in two consecutive trials with 3 animals per trial. The test atmosphere was generated by bubbling 200 L/h dry air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder. The temperature in the exposure chamber was 20°C. The concentration of the test atmosphere was stated to be 0.15 mg/L, an analytical verification was not performed. As the calculated vapour saturation is 0.357 mg/L (vapour pressure: 0.05 hPa at 20°C), vapour saturation was eventually not completed. The animals were observed daily for 7 days for clinical signs and mortality. Weighing was performed only at the beginning of the study. No mortality resulted from the exposure to the test atmosphere. No clinical signs and no abnormalities at necropsy were observed.

In the second inhalation hazard test (IHT) by BASF (No. XV/127, 1965), 6 male and 6 female rats were exposed to a test atmosphere saturated with vapours of test substance for 8 hours in two consecutive trials with 3 animals per trial. The test atmosphere was generated by bubbling 200 L/h dry air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder. The temperature in the exposure chamber was 20°C. The concentration of the test atmosphere was stated to be 0.54 mg/L, an analytical verification was not performed. As the calculated vapour saturation is 0.357 mg/L (vapour pressure: 0.05 hPa at 20°C), aerosol formation could not be excluded. The animals were observed daily for 7 days for clinical signs and mortality. Weighing was performed at the beginning and end of the study and the animals gained body weight. No mortality resulted from the exposure to the test atmosphere. No clinical signs and no abnormalities at necropsy were observed.

Smyth et al. (1954) investigated the inhalative toxicity by exposing 6 male and 6 female rats to a flowing stream of air approaching saturation with vapours for 8 hours. The stream was prepared by passing dried air through a fritted disc gas washing bottle initially at room temperature (analytical verification was not performed). No mortality was observed. Data on clinical signs, body weights or necropsy were not given.

In conclusion, all four Inhalation Hazard Tests conducted with the source substance indicate that a saturated atmosphere at ambient temperature does not induce mortality. Therefore, there is no need to conduct further inhalation studies for the determination of an acute LC50 after exposure to vapours of the target substance Butyldiethanolamine.

Acute toxicity: dermal

The study was performed to assess the acute dermal toxicity of Butyldiethanolamine in the Wistar strain rat (Harlan Laboratories, 2014; Report No. 41402071). A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths or signs of systemic toxicity. Very slight erythema was noted at the test sites of one male and four females. Small superficial scattered scabs and glossy skin were also noted at the test sites of four females. There were no signs of dermal irritation noted at the test sites of four males and one female. All animals showed expected gains in body weight. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.


Justification for selection of acute toxicity – oral endpoint
Best study available

Justification for selection of acute toxicity – inhalation endpoint
No inhalation studies need to be conducted.

Justification for selection of acute toxicity – dermal endpoint
Best study available

Justification for classification or non-classification

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the LD50 of ca. 4800 mg/kg bw and LD50 of greater than 2000 mg/kg bw for oral and dermal toxicity, respectively, classification and labelling is not warranted for these routes. Based on the results of the acute toxicity inhalation tests available for the source substances BEA (CAS 111 -75 -1) and DBEA (CAS 102 -81 -8), classification and labelling is not warranted for the target substance Butyldiethanolamine for inhalation route.

In the acute inhalation study with BEA (CAS 111 -75 -1), mucous membrane irritation was observed in treated animals by inhalation during 8 hours. However, due to the low volatility of the target substance Butyldiethanolamine (vapour pressure of 1.2 Pa at 25 °C indicates low volatility according to ECHA guidance R.7.c, 2014 on Toxicokinetics) inhalation is not a relevant route of exposure. Therefore, classification and labelling for STOT-SE (Cat 3; H335, May cause respiratory irritation) is not triggered according to Regulation (EC) No.1272/2008.