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Description of key information

Acute toxicity: Oral LD50 between 300 and 2000 mg/kg for rat (LD50 cut-off: 500 mg/kg bw).

No data is available on acute toxicity via inhalation or dermal route.

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:
5-23 June 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: approx. 9-10 weeks old
- Weight at study initiation: 170-200 grams. Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: yes, overnight prior to dosing and until 3-4 hours after administration of the test substance
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:at least 5 days before start of treatment under laboratory conditions


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.4 – 21.0ºC
- Humidity (%): 40 - 73%
- Air changes (per hr): approx.15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 5 June 2009 To: 23 June 2009
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 300 mg/kg: 30 mg/mL, and 2000 mg/kg: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


DOSAGE PREPARATION (if unusual):
The formulations (w/w) were prepared within 4 hours prior to dosing, and were flushed with nitrogen. Homogeneity was accomplished to a visually acceptable level. In order to obtain homogeneity, the test substance formulations were heated in a water bath with a maximum temperature of 45ºC for a maximum of 11 minutes. The test substance (formulations) were allowed to cool down to a temperature of maximally 40ºC prior to dosing. Adjustment was made for specific gravity of the vehicle and for density of the test substance. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on anticipated toxicity at 2000 mg/kg.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
300 mg/kg: two groups of 3 females
2000 mg/kg: one group of 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. Weighing: Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
- Necropsy of survivors performed: yes
- Other examinations performed: none.
Statistics:
Not applicable.

Preliminary study:
Not applicable
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Mortality:
The incidence of mortality was as follows, presented in chronological order of treatment:
Dose level Mortality Date of treatment
300 mg/kg 0/3 05 June 2009
300 mg/kg 0/3 09 June 2009
2000 mg/kg 3/3 16 June 2009

The decedents were found on Day 2 or 4 post-treatment.
Clinical signs:
Animals at 300 mg/kg showed hunched posture, uncoordinated movements and/or piloerection between days 1 and 3.

Animals at 2000 mg/kg showed hunched posture, lethargy, piloerection, uncoordinated movements, laboured respiration, rales, ptosis, hypothermia, watery discharge from the eyes and/or chromodacryorrhoea prior to death.
Body weight:
The body weight gain shown by animals at 300 mg/kg/day over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Animals at 2000 mg/kg showed weight loss of reduced weight gain prior to death.
Gross pathology:
One animal at 2000 mg/kg showed a stage of beginning autolysis. No macroscopic abnormalities were noted in the other animals at 2000 mg/kg, and in the animals at 300 mg/kg.
Other findings:
None

None.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of Oleyl dipropylenetriamine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight, with a cut-off value of 500 mg/kgbw.
Executive summary:

Oleyl dipropylenetriamine (Triameen OV) was tested for acute oral toxicity by Acute Toxic Class method. Test substance was dissolved in PG and dosed by gavage at 10 mL/kg bw.

The incidence of mortality was as follows, presented in chronological order of treatment:

Dose level                    Mortality                       Date of treatment

300 mg/kg                    0/3                               05 June 2009

300 mg/kg                    0/3                               09 June 2009

2000 mg/kg                  3/3                               16 June 2009

The decedents were found on Day 2 or 4 post-treatment.

Animals at 300 mg/kg showed hunched posture, uncoordinated movements and/or piloerection between days 1 and 3.

Animals at 2000 mg/kg showed hunched posture, lethargy, piloerection, uncoordinated movements, laboured respiration, rales, ptosis, hypothermia, watery discharge from the eyes and/or chromodacryorrhoea prior to death.

The body weight gain shown by animals at 300 mg/kg/day over the study period was considered to be normal.

Animals at 2000 mg/kg showed weight loss of reduced weight gain prior to death.

One animal at 2000 mg/kg showed a stage of beginning autolysis. No macroscopic abnormalities were noted in the other animals at 2000 mg/kg, and in the animals at 300 mg/kg.

The oral LD50value of Oleyl dipropylenetriamine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
Guideline studies (OECD 423) under GLP. All data show consistent results over the group of polyamines.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Scientific and exposure related waiving: Corrosive and low likelihood for exposure via inhalation.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Scientific and exposure related waiving: Corrosive and low likelihood for exposure.

Additional information

Acute oral toxicity:

Oleyl dipropylenetriamine (Triameen O) was tested for acute oral toxicity by Acute Toxic Class method. At 300 mg/kg animals showed hunched posture, uncoordinated movements and/or piloerection between days 1 and 3. No mortality occurred and body weight development was normal.

At 2000 mg/kg all animals showed hunched posture, lethargy, piloerection, uncoordinated movements, laboured respiration, rales, ptosis, hypothermia, watery discharge from the eyes and/or chromodacryorrhoea prior to death. All animals were found dead on Days 2 or 4.

One animal at 2000 mg/kg showed a stage of beginning autolysis. No macroscopic abnormalities were noted in the other animals at 2000 mg/kg, and in the animals at 300 mg/kg.

The oral LD50 value of Oleyl dipropylenetriamine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight, with a cut-off value of 500 mg/kgbw.

 

Comparable other triamines (alkyl dipropylenetriamine) and tetramines (alkyl tripropylenetatramine) show similar results, where those with on average shorter alkyl chains show a somewhat higher toxicity compared to those with longer alkyl chain lengths:

Acute toxicity Triamines:

           Coco   50-300 mg Cat.3; cut off 200

           Tallow  300-2000 mg Cat.4; cut of 500

           Oleyl    300-2000 mg Cat.4; cut of 500

Acute toxicity Tetramines:

           Tallow  300-2000 mg Cat.4; cut of 500

           Oleyl    300-2000 mg Cat.4; cut of 1000

 

In conclusion, there is little effect of the actual number propylene amine groups between linear triamine or linear tetramine. With increasing length of the alkyl chain, the acute toxicity decreases.

 

Acute dermal toxicity:

Polyamines are corrosive to the skin. Testing for acute dermal toxicity is therefore not justified. Toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material.

The mode of action of for polyamines follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine linked to a secondary amine. The structure can disrupt the cytoplasmic membrane, leading to lyses of the cell content and consequently the death of the cell.

The polyamines are completely protonated under environmental conditions which causes them to strongly adsorb to organic matter. This all leads to a low dermal absorption as is shown by a dermal absorption study performed on a structurally related branched triamine (Dodecyl dipropylenetriamine, CAS 2372-82-9) for 24 hours, resulted in a dermal penetration of less than 0.01% whereas 0.92% of the applied dose did pass the stratum corneum but remained further fixed in the skin (Report not included in this dossier)

For the linear polyamines a similar and even lower (in case of higher alkyl chain lengths) dermal penetration can be expected.

 

Acute inhalation toxicity:

Physical-chemical properties of Oleyl dipropylenetriamine indicate a low likelihood for exposure via inhalation. The substance has a boiling point > 300 °C and a low vapour pressure (4.7 x 10-5 Pa at 20°C for the coco dipropylenetriamine, with the shortest average alkyl chain length representing the highest vapour pressure for this group of polyamines). Its use is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. So exposure to humans via the inhalation route will be unlikely to occur. Furthermore, as the substance is classified as corrosive, such testing should normally not be conducted.

Justification for classification or non-classification

Acute oral exposure of Oleyl tripropylenetetraamine leads to harmful effects, with a LD50 between 300 and 2000 mg/kg bw. The substance therefore need to classified as “ Cat.4 harmful if swallowed” for acute oral toxicity for GHS.

 

Acute dermal testing with these very corrosive materials is not justified. As a consequence no classification can be made for acute dermal toxicity. Effects will be characterised by local tissue damage. Systemic uptake via skin is likely to be very limited.

 

Also for acute inhalation toxicity information for classification is lacking, and is testing not justified. The likelihood of exposure via inhalation low.

 

No classification STOT-SE Cat.3 needed:

Polyamines are not structurally related to any known class of neurotoxic chemicals. In addition, repeated dose studies did not show indications of specific neurotoxicity, in specific neurotoxicity measures as sensory activity, grip strength, and motor activity assessment.

 

Polyamines do not contain containing aliphatic, alicyclic and aromatic hydrocarbons and so do not indicate an immediate concern for aspiration hazard.