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Administrative data

Description of key information

Acute Toxicity:
- oral: LD50: 1008 mg/kg bw (rat; BASF AG 1967)
- dermal: LD50: 956 mg/kg bw (rabbit; Union Carbide 1968)
- inhalation: LC50: 0.91 mg/L air (rat; BASF AG 1991)

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:
05. Jun 1967 - 14. Jun 1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented report which meets basic scientific principles.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(adopted 1981)
Deviations:
yes
Remarks:
(7 day observation period; highest dose tested was 1612 mg, but all animals of this dose group - besides one male animal - died)
Principles of method if other than guideline:
BASF-Test. The study was conducted according to an internal BASF method which in principle is comparable to the OECD Guideline 401.
A test group consisting of 5 animals/sex was treated by single gavage with an aqueous solution of the test substance. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 7 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy. The LD50 value was estimated on the basis of the observed mortalities.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: US-rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 254 g (mean), female: 206 g (mean).
Route of administration:
oral: gavage
Vehicle:
other: aqueous Traganth solution
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2% (161 mg/kg bw), 20% (806, 1008, 1290, 1612 mg/kg bw)

MAXIMUM DOSE VOLUME APPLIED: 6.25 ml (1250 mg/kg bw), 5 ml (1000 mg/kg bw), 8 ml (1600 mg/kg bw), 10 ml (200 / 2000 mg/kg bw)

Doses:
161, 806, 1008, 1290, 1612 mg/kg bw (= 200, 1000, 1250, 1600, 2000 mL/kg bw ; calculation of doses in mg/kg bw by means of density = 0.8062 g/mL)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 1 008 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Systemic toxicity (including mortality) and local irritation observed; see descritpions below for details
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 1 149 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 847 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Females appeared to be more sensitive.
Mortality:
1612 mg/kg bw: 1 male died within 24 h. 3 males and 5 females died within 48 h. 4 males died within 7 days. 1 male animal survived.
1290 mg/kg bw: 1 male and 3 females died within 24 h. 2 males and 4 females died within 48 h. 5 males and 5 females died within 7 days.
1008 mg/kg bw: 2 females died within 24 h. 5 females died within 48 h. All males survived.
806 mg/kg bw: 1 female died within 7 days. All other animals survived.
161 mg/kg bw: No animal died.
Clinical signs:
1612 – 806 mg/kg bw: Irregular / accelerated respiration, heavy ruffled fur, anogenital region smeared with feces (diarrhea), squatting posture, apathy, red eye and nose crusts. The survivors recovered.
161 mg/kg bw: Same but less distinct symptoms as in higher dose groups. 24 h post treatment the animals were considered as normal.
Body weight:
no data
Gross pathology:
dead animals (806 - 1612 mg/kg bw): Dilated stomach in 18 cases, atony in 8 cases, and blood smeared snouts.

sacrificed animals: Uneven faded liver, adhesion between liver, stomach, spleen and left kidney; bronchitis, bronchopneumonia with emphysema.

Mortality

 Dose (mg/kg bw) Gender  1 h  24 h  48 h  7 days  
1612 male  0/5  1/5 3/5  4/5    
  female  0/5  0/5  5/5  5/5    
1290 male  0/5  1/5  2/5  5/5  
  female  0/5  3/5  4/5  5/5  
1008 male  0/5 0/5  0/5 0/5  
  female  0/5 2/5  5/5  5/5   
806 male  0/5  0/5  0/5  0/5    
  female   0/5  0/5  0/5  1/5  
161 male   0/5  0/5  0/5  0/5    
  female  0/5  0/5  0/5  0/5    

The test substance caused systemic toxicity (including mortality) and local irritation in a dose dependent manner.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The study on acute oral toxicity of Di-2-ethylhexylamin in male and female US-rats resulted in a LD50 value for both sexes of 1008 mg/kg bw. The female animals appeared to be more sensitive. A classification according to the CLP Regulation (EC) No. 1272/2008 (EU-GHS: Cat. 4) is required.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 008 mg/kg bw
Quality of whole database:
Available data is reliable and sufficient for assessment.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(adopted 1981)
Deviations:
no
GLP compliance:
yes
Remarks:
BASF AG, Department of Toxicology
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain as named in the report: SPF Wistar/Chbb: THOM
- Source: Dr. K. Thomae GmbH, Biberach, FRG
- Age at study initiation: approximately 8-9 weeks
- Weight at study initiation: males: 260 ± 12.1 g (mean), female: 181 ± 5.7 g (mean)
- Housing: in groups of five, in cages type DK III of Becker
- Diet: KLIBA rat/mouse laboratory diet 24-343-4, 10 mm pellets, Klingenthalmuehle AG, Kaiseraugst, Switzerland, ad libitum
- Water: ad libitum (during the post-exposure observation period)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- 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:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction, BASF AG)
- Exposure chamber volume: 55 L
- Method of holding animals in test chamber: The animals were restrained in tubes and their snouts projected into the inhalation chamber.
- Source and rate of air: 1500 L/h
- System of generating particulates/aerosols: A liquid aerosol was generated by means of a continuous infusion pump INFU 362 (INDIGEL/Switzerland) and a two-component atomizer Mod. 970 (Schlick). By means of compressed air the aerosol was generated, which was passed into the inhalation system.
- Method of particle size determination: gas chromatography
- Treatment of exhaust air: By means of an exhaust air system the pressure ratios in the inhalation system were adjusted in such a way that the amount of exhaust air was about 10 % lower (excess pressure). This ensured that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals.
- Temperature in air chamber: 19 - 25 °C

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography (from the analytically determined mass values and the sample volumes of the inhalation atmosphere the concentrations were calculated in mg/L).
- Samples taken from breathing zone: yes


Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatography
Duration of exposure:
4 h
Concentrations:
- analytical: 0.28 mg/L (test group 1), 0.53 mg/L (test group 2), 0.84 mg/L (test group 3), 1.28 mg/L (test group 4), 2.85 mg/L (test group 5)
- nominal: 0.54 mg/L, 0.97 mg/L, 1.61 mg/L, 3.11 mg/L, 5.37 mg/L
No. of animals per sex per dose:
5
Control animals:
other: historical controls
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: at least once on each workday
- Frequency of weighing: Before the beginning of the test, after 7 days (test groups 1, 2, 4 and 5), after 8 days (test group 3) and at the end of the observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The statistical evaluation of the dose-response relationship was carried out using FORTRAN program AKPROZ.
The calculation of the particle size distribution was carried out in the Department of Toxicology of BASF AG on the basis of mathematical methods
for evaluating particle measurements (DIN 66141: Darstellung von Korngroeßenverteilungen, DIN 66161: Partikelgroeßenanalyse).
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.91 mg/L air
Based on:
test mat.
95% CL:
> 0.73 - < 1.19
Exp. duration:
4 h
Remarks on result:
other: Systemic toxicity (including mortality) and local irritation observed; see descriptions below for details
Mortality:
0.28 mg/L: no mortalities occurred.
0.53 mg/L: 1 male died on day 2.
0.84 mg/L: 2 males and 1 female died on day 2 and a further female died until day 7.
1.28 mg/L: 2 males and all 5 females died on day 0 and a further male died on day 2.
2.86 mg/L: all animals died within 3 h of exposure.
Clinical signs:
other: During exposure: 0.28 mg/L: initially escape attempts; irregular respiration until the end of exposure. 0.53 mg/L: initially escape attempts and accelerated respiration; whooping respiration; intermittent respiration and decreased pain reflex until the e
Body weight:
The body weight gain of the female rats in the test group 1, compared with a historical control collective, was not affected by the substance over the total observation period.
The body weight gain of the male rats in the test groups 1, 2, 3, compared with a historical control collective, was slightly retarded in the first week of the observation period and adjusted to normal in the second week of the observation period.
The body weight gain of the female rats in the test group 2, compared with a historical control collective, was slightly retarded in the second week of the observation period.
The body weight gain of the female rats in the test group 3, compared with a historical control collective, was reduced over the total observation period.
The body weight gain of the male animals in the test group 4, compared with a historical control collective, was reduced in the first week of the observation period and adjusted to normal in the second week of the observation period. The animals did not, however, reach the body weight which they had before exposure.
Gross pathology:
Animals that died spontaneously:
All groups: general congestion.
0.53, 0.84, 1.28 mg/L: lungs: intensified focal hyperemia, additional moderate emphysema.
1.28 mg/L: liver: slightly marked grey brown lobules.
2.85 mg/L: lungs: intensified hyperemia with edema.

Sacrificed animal: no pathologic findings noted.

Mortality:

 Dose (mg/L)  Gender  Day 0  Day 1  Day 2  Day 7  Day 14
 0.28  male  0/5  0/5 0/5  0/5  0/5 
 0.28  female  0/5  0/5 0/5  0/5  0/5 
 0.53  male  0/5  0/5 1/5 1/5 1/5
 0.53  female  0/5  0/5 0/5 0/5 0/5
 0.84  male  0/5 0/5  2/5 2/5 2/5
 0.84 female  0/5  0/5 1/5 2/5 2/5
 1.28 male   2/5  2/5 3/5 3/5 3/5 
 1.28  female  5/5 5/5 5/5  5/5  5/5 
 2.86  male  5/5  5/5 5/5  5/5  5/5 
 2.86  female  5/5 5/5 5/5  5/5  5/5 

Body weight:

 Mean body weight (in g)   male        female     
   0 days  7 days  14 days  0 days  7 days  14 days
 0.28 mg/L 269 281 324  183  196  207 
0.53 mg/L 265  274  314  181  194  201 
 0.84 mg/L 262  263  314  182  176  175 
 1.28 mg/L 257  194  226  179 
2.86 mg/L 251   - 179
 historical control 248  286  318  177  196  211 

"-": all animals dead.

Particle size analysis:

Test group MMAD 50% [µm] GSD Respirable fraction [%]
1 1.6 3.3 95
2 1.5 3.4 95
3 1.7 3.5 93
4 1.4 3.8 94
5 1.8 3.7 93
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The study on acute inhalation toxicity of Di-2-ethylhexylamine as an aerosol in male and female Wistar rats resulted in a LC 50 value for both sexes of 0.91 mg/L after an exposure period of 4 hours and an observation period of 14 days. The particle size analysis revealed that the amount of respirable fraction was very high. A classification according to the CLP Regulation (EC) No. 1272/2008 (EU-GHS: Cat. 3) is required.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
910 mg/m³
Quality of whole database:
Available data is reliable and suffidcient for assessment.

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
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Only secondary source.
Principles of method if other than guideline:
no data
GLP compliance:
not specified
Test type:
other: no data
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
not specified
Duration of exposure:
no data
Doses:
no data
No. of animals per sex per dose:
no data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
956 mg/kg bw
Based on:
test mat.
Remarks on result:
other: = 1190 µL/kg bw (calculation of the dose in mg/kg bw by means of the density at 20°C: 0.803 g/cm³)
Mortality:
no data
Clinical signs:
no data
Body weight:
no data
Gross pathology:
no data

Of pronounced toxicity after a short term skin contact.

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The study on acute dermal toxicity of bis(2-ethylhexyl)amine in rabbits resulted in a LD50 value of 956 mg/kg bw. No further information given. A classification according to the CLP Regulation (EC) No. 1272/2008 (EU-GHS: Cat. 3) is required.
Executive summary:

A dermal LD50 value of 1.19 mL/kg, equivalent to 956 mg/kg bw, was reported for rabbits, with no further details, because data were only available as secondary quotation cited in RTECS updates 9504 and 199709 (Union Carbide 1968; reliability score 4).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
956 mg/kg bw
Quality of whole database:
Only secondary source, but two routes are covered and additionally, the test substance is corrosive. Therefore, it is assumed that the available data is sufficient for assessment.

Additional information

Oral:

In an acute oral toxicity study (BASF AG 1967; reliability score 2) groups of US rats (5 / sex) were given a single oral dose (via gavage) of the test substance in aqueous Traganth solution at doses of 200, 1000, 1250, 1600, 2000 mg/kg bw and observed for 7 days.

Oral LD50Males = ca. 1149 mg/kg

Oral LD50Females = ca. 847 mg/kg bw

Oral LD50Combined = ca. 1008 mg/kg bw

 

The female animals appeared to be more sensitive. Main clinical signs observed were irregular / accelerated respiration, heavy ruffled fur, anogenital region smeared with feces (diarrhea), squatting posture, apathy, red eye and nose crusts. All survivors recovered. At necropsy of the dead animals, dilated stomach, atony and blood smeared snouts were observed. The sacrificed animals showed uneven faded liver, adhesion between liver, stomach, spleen and left kidney; bronchitis or bronchopneumonia with emphysema.

 

In a range finding toxicity publication of Smyth et al., groups of 5 rats (gender unspecified) received 4 dosages in geometrical series, with a ratio 2 between successive dose levels, and were observed for 14 days; a LD50 of 1640 mg/kg bw (Smyth et al. 1949; reliability score 2).

Dermal:

A dermal LD50 value of 1.19 mL/kg, equivalent to 956 mg/kg bw was reported for rabbits, with no further details provided, because data were only available as secondary quotation cited in RTECS updates 9504 and 199709 (Union Carbide 1968; reliability score 4).

According to REACH Regulation Annex VIII, 8.5 acute toxicity studies does not need to be conducted if the substance is classified as corrosive and in addition to the oral route informations according to acute toxicity shall be provided for at least one other route, respectively. Informations concerning acute toxicity via oral and inhalative route are provided. Additionally, the test substance is classified as corrosive. Therefore, it is concluded that the available information is sufficient and no further acute dermal toxicity study is necessary.

 

Inhalation:

Acute inhalation toxicity was analyzed in study performed according to OECD Guideline 403 (BASF AG 1991; reliability score 2).Groups of young adultWistar rats (5/sex) were dosed with the test substance as aerosol at concentrations of 0.28 mg/L, 0.53 mg/L, 0.84 mg/L, 1.28 mg/L or 2.85 mg/L for 4 hours (nose/head only). Animals then were observed for 14 days.

 

LC50Combined = 0.91 mg/L (95% C.I..: 0.73 – 1.19 mg/L)

 

Main clinical signs observed were local irritation of the airways and of the eyes. 30 min post application tonic-clonic convulsions, restlessness, pain reflex and intermittent respiration were noted. Also effects on body weight were noted. At necropsy, general congestion and pulmonary hyperemia with edema were observed.

Additional data were available from inhalation risk tests (IRT). The inhalation of a saturated vapour-air mixture (0.2 mg/L) for 8 h caused no mortality in male and female rats (strain not specified). Symptoms described included signs of irritation of the mucous membranes and post mortem examination revealed occasional bronchopneumonia (BASF AG 1967; reliability score 2).

In a second IRT, groups of six male albino rats (strain unspecified) were exposed to a flowing stream of air substantially saturated with vapours of the test material. No mortality was observed (Smyth et al. 1949; reliability score 2).

Due to the results of the inhalation studies there is evidence that the test substance is strongly irritating, at high concentrations corrosive, to the respiratory system. Additionally, a study was conducted to characterize the respiratory irritation potential caused by the test substance qualitatively and quantitatively (calculation of RD50; BASF AG 1998; reliability score 2). Groups of 4 male Swiss mice were placed individually in whole body plethysmographs connected to a head-nose inhalation system. After an adaption phase of ten minutes and a control phase of 15 minutes, the animals were exposed to analytically determined concentrations of 7.88, 32.6 and 48.6 mg/m3(0.8, 3.3 and 4.8 ppm) test substance vapours for 45 minutes. The exposure phase was followed by a recovery phase of 15 minutes. A post exposure observation period lasting 7 days was also included in the study. Respiratory parameters were measured in each animal during control, exposure and recovery period and the RD50was calculated.A considerable decrease of RD50value occurred with prolongation of exposure. In each concentration used, the respiratory depression was not reversible during the recovery phase. No clinical signs and no abnormalities were detected during necropsy. No changes of lung weights occurred in the exposed animals as compared to control. It was concluded that the test substance led mainly to pulmonary irritation.


Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – inhalation endpoint
Key study

Justification for selection of acute toxicity – dermal endpoint
Only one study available without detailed information.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The reliable oral toxicity studies led to classification according to Regulation (EC) No.1272/2008 (EU-GHS: Cat. 4).

Regarding the results of the dermal test classification according to Regulation (EC) No.1272/2008 (EU-GHS: Cat. 3) is required.

Due to the reliable results of the inhalation studies classification according to Regulation (EC) No.1272/2008 (EU-GHS: Cat.3) is required.