N-(3-aminopropyl)-N- (C12-18 even numbered) alkyl-propane-1,3-diamine

Endpoint summary

Description of key information

Acute toxicity: Oral LD50 between 50 and 300 mg/kg for rat. The LD50 cut-off is 200 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:

05 June 2009 - 01 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 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:

None.

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. 8-10 weeks old
- Weight at study initiation: 148-183 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 - 79%
- Air changes (per hr): approx.15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 05 June 2009 To: 01 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 50 mg/kg: 5 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 43ºC 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 50 mg/kg

No. of animals per sex per dose:

300 mg/kg: one group of 3 females
50 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

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 cut-off = 200 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 3/3 05 June 2009
50 mg/kg 0/3 09 June 2009
50 mg/kg 0/3 17 June 2009

The decedents were found on Day 2 post-treatment.

Clinical signs:

other: Animals at 300 mg/kg showed lethargy, hunched posture, uncoordinated movements, piloerection and/or ptosis prior to death. Animals at 50 mg/kg showed hunched posture, salivation, piloerection and/or rales between days 1 and 6.

Gross pathology:

Two animals at 300 mg/kg showed a stage of beginning autolysis, along with red foci on the glandular mucosa in one of these animals. No macroscopic abnormalities were noted in the other animal at 300 mg/kg, and in the animals at 50 mg/kg.

Other findings:

none.

none.

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The oral LD50 value of Coco dipropylene triamine in Wistar rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 mg/kg body weight.

Executive summary:

The acute toxicity of Cocodipropylenetriamine was determined according to OECD Guideline 423 in compliance with GLP. A group of young female rats received an oral gavage dose of the test substance in propylene glycol (10 mL/kg bw), at a dose level of 300 (one test group comprising 3 females) and 50 mg/kg bw (two test groups comprising 3 females).

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

Dose level                    Mortality

300 mg/kg                    3/3

50 mg/kg                      0/3

50 mg/kg                      0/3

 

The decedents were found on Day 2 post-treatment.

 

Animals at 300 mg/kg showed lethargy, hunched posture, uncoordinated movements, piloerection and/or ptosis prior to death.

Animals at 50 mg/kg showed hunched posture, salivation, piloerection and/or rales between days 1 and 6.

 

Animals found dead at 300 mg/kg showed slight body weight loss. 

The body weight gain shown by the animals at 50 mg/kg over the study period was considered to be normal.

 

Two animals at 300 mg/kg showed a stage of beginning autolysis, along with red foci on the glandular mucosa in one of these animals. No macroscopic abnormalities were noted in the other animal at 300 mg/kg, and in the animals at 50 mg/kg.

 

The oral LD50 value of cocodipropylene triamine in Wistar rats was established to be within the range of 50-300 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

200 mg/kg bw

Quality of whole database:

Reliable Guideline study (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:

The acute toxicity of Cocodipropylenetriamine was determined according to OECD Guideline 423 in compliance with GLP. A group of young female Wistar rats received an oral gavage dose of the test substance in propylene glycol (10 mL/kg bw), at a dose level of 300 (one test group comprising 3 females) and 50 mg/kg bw (two test groups comprising 3 females).

All animals of the 300 mg/kg bw group showed hunched posture from one hour after dosing, piloerection from 2 hours after dosing, and lethargy, uncoordinated movements and/or ptosis 4 hours after dosing. All animals were found dead the day after administration. Two animals at 300 mg/kg showed a stage of beginning autolysis, along with red foci on the glandular mucosa in one of these animals. No macroscopic abnormalities were noted in the other animal at 300 mg/kg.

All animals treated with 50 mg/kg bw survived, and showed hunched posture, salivation, piloerection and/or rales between days 1 and 6. The body weight gain shown by the animals at 50 mg/kg over the study period was considered to be normal. No macroscopic abnormalities were noted

The oral LD50 value of cocodipropylenetriamine in Wistar rats was established to be within the range of 50-300 mg/kg body weight. The LD50 cut-off is set at 200 mg/kg bw based on the mortality of all three animals at first step at 300 mg/kg.

 

Acute inhalation toxicity:

Physical-chemical properties of Cocodipropylenetriamine 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).

In accordance with Annex VIII Column 2 of REACH, the acute toxicity study by inhalation does not need to be conducted as the test substance has a low vapour pressure. Furthermore, as the substance is classified as corrosive, such testing should normally not be conducted.

Besides, no testing is required for on-site isolated intermediates handled under SCC.

 

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.

Justification for selection of acute toxicity – oral endpoint
Only one guideline-compliant study is available.

Justification for selection of acute toxicity – inhalation endpoint
: Low likelihood for exposure via inhalation; bp > 300 ºC and vapour pressure 0.05 mPa at 20°C.

Justification for selection of acute toxicity – dermal endpoint
In accordance with column 2 of REACH Annex VIII, the acute dermal toxicity study does not need to be conducted when the substance is classified as corrosive to the skin.

Justification for classification or non-classification

Based on an acute oral LD50 cut-off of 200 mg/kg bw, Cocodipropylenetriamine qualifies for classification Acute Tox. 3 (H301 - Toxic if swallowed.) according to Regulation (EC) 1272/2008.

 

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 is 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.