Amines, N-(3-aminopropyl)-N'-(C16-18 and C18-unsatd. alkyl)trimethylenedi-

Endpoint summary

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:

24 June 2009 - 14 July 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study has been performed according to OECD and/or EC guidelines and according to GLP principles.

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

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. 9-11 weeks old
- Weight at study initiation: 155-186 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 (%): 41 - 79%
- Air changes (per hr): approx.15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 24 June 2009 To: 14 July 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 (except the 2000 mg/kg formulation; this was considered not to have adversely affected integrity of the test substance as the test substance itself was flushed with nitrogen and formulated in vehicle afterwards). 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 44ºC for at least 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:

2000 mg/kg: one group of 3 females
300 mg/kg: two groups 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

Sex:

female

Dose descriptor:

LD50

Effect level:

500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: OECD 423 Cut-off level

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 24 June 2009
300 mg/kg 0/3 30 June 2009
2000 mg/kg 3/3 02 July 2009

At 2000 mg/kg, animals were found dead or sacrificed in moribund condition on Days 2 or 3.

Clinical signs:

other: Clinical signs observed during the study period were as follows: Dose level Clinical signs 300 mg/kg Hunched posture, piloerection, lethargy, chromodacryorrhoea on Days 1 and/or 2. 2000 mg/kg Hunched posture, piloerection, lethargy, ptosis.

Gross pathology:

An advanced stage of autolysis was noted for one animal at 2000 mg/kg found dead on Day 3.
No further abnormalities were found at macroscopic post mortem examination of the animals.

Other findings:

None.

None.

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: other: GHS, EU 67/548/EEC and 1272/2008

Conclusions:

The oral LD50 value of Tallow dipropylenetriamine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
OECD 423 LD50 cut-off value is 500 mg/kg body weight.

Executive summary:

All animals at 2000 mg/kg were found dead or were sacrificed moribund on Days 2 or 3. At 300 mg/kg, no mortality occurred.                             

Clinical signs observed during the study period were as follows:

Dose level                    Clinical signs

300 mg/kg                    Hunched posture, piloerection, lethargy, chromodacryorrhoea on Days 1 and/or 2.

2000 mg/kg                  Hunched posture, piloerection, lethargy, ptosis.

Slight body weight loss was noted for all animals at 2000 mg/kg prior to death.

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

An advanced stage of autolysis was noted for one animal at 2000 mg/kg found dead on Day 3.

No further abnormalities were found at macroscopic post mortem examination of the animals.

The oral LD50value of Tallow 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

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

Tallow dipropylenetriamine (Tallow triamine) was tested for acute oral toxicity by Acute Toxic Class method. At 300 mg/kg animals showed hunched posture, piloerection, lethargy and chromodacryorrhoea on days 1 and/or 2 of the observation period. No mortality occurred and body weight development was normal.

At 2000 mg/kg all animals showed hunched posture, piloerection, lethargy, and ptosis. All animals were found dead or sacrificed in moribund condition on Days 2 or 3.

An advanced stage of autolysis noted for one animal at 2000 mg/kg found dead on day 3. Macroscopic post mortem examination of all other animals showed no abnormalities.

 

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 dipropylene triamine) 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[IRI report No.: 204648, 2003, The In vitro percutaneous absorption of [14C]-N-(3 -aminopropyl) -N-dodecylpropane -1,3 -diamine through human skin].

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 C16-18, C18-unsaturated-alkyl dipropylene triamine indicate a low likelihood for exposure via inhalation. The paste has a boiling point > 300 °C and a low vapour pressure (4.7 x 10-5 Pa at 20°C for the coco dipropylene triamine, with the shortest average alkyl chain length representing the highest vapour pressure for the 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 Tallow dipropylenetriamine 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.