Amines, N-(3-aminopropyl)-N’-[3-(C16-18 (even numbered) and C18 unsaturated alkyl amino)propyl]trimethylenedi- and amines, N-(3-aminopropyl)-N’-(C16-18 (even numbered) and C18 unsaturated 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:

14 January 1987 - 28 January 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A study was performed under GLP and generally according to OECD 401, but not using 5 animals of one sex per group. Limited data on test substance identity; no data on batch number, no Certificate of Analysis.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Instead of "At least 5 rodents are used at each dose level. They should all be of the same sex", in this study 4 rats are used per dose level, 2 male and 2 female animals.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, FRG
- Age at study initiation: 7 weeks
- Weight at study initiation: males on day 0 ranged from 271 to 306 g, females from 174 to 210 g
- Fasting period before study: overnight
- Housing: individually housed i n polycarbonate cages
- Diet (e.g. ad libitum): ad libitum,standard laboratory animal diet (RMH-B, pellet diameter 10 mm), obtained from Hope Farms, Woerden, The Netherlands.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-75
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 January 1987 To: 28 January 1987

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10ml/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10ml/kg

DOSAGE PREPARATION (if unusual):
On the day of dosing the test substance was suspended in propylene glycol and heated to 35ºC in order to get a homogeneous suspension and administered as a single dose using a stainless steel stomach cannula.

Doses:

25, 200, 2000 mg/kg bw

No. of animals per sex per dose:

2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Cage-side observations were performed on the day of dosing (once every two hours) and daily thereafter. Individual body weights (with group means) were measured weekly. Body weights were also measured at death when found dead 24 hours or more following dosing.
- Necropsy of survivors performed: yes
- Other examinations performed: none

Statistics:

none

Preliminary study:

not performed

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 200 - < 2 000 mg/kg bw

Mortality:

At 2000 mg/kg bw all animals died. One on the day of dosing and the others on day 1. At the other dose levels no deaths occurred.

Clinical signs:

other: Signs of toxicity, lethargy and a rough fur, were only observed in animals of the high dose group. At the other dose levels no signs of toxicity were observed.

Gross pathology:

Macroscopic examination o f animals at necropsy showed no abnormalities in the low and mid dose group and petechiae; a yellow liquid intestinal content and gas accumulation in the intestines in all animals of the high dose group.

Other findings:

none

Conclusions:

The oral LD50 value of Tallow tripropylene tetramine in Wistar rats is within the range of 300-2000 mg/kg body weight.
LD50 cut-off value is 500 mg/kg body weight.

Executive summary:

Three groups of Wistar rats; each comprising 2 males and 2 females, received a single oral dose at 25, 200 and 2000 mg/kg body weight; respectively. The incidence of mortalities for the sexes combined from low to high dose group was 0, 0 and 4. There was no evident sex related effect. All deaths occurred within 1 day of dosing. Signs of toxicity in animals of the high dose group were lethargy and a rough fur. No abnormal clinical behaviour was observed in animals of the 25 mg/kg and 200 mg/kg dose groups and no abnormalities at necroscopy. Group mean body weight gain for animals of the low and mid dose groups was nomal. Macroscopic examination of animals at necropsy revealed in all animals of the high dose group petechiae of the stomach, a yellow liquid intestinal content and gas accumulation in the intestines.

Based on the absence of signs of toxicity in the 200 mg/kg group as well as the absence of abnormalities in this group at necroscopy, it is considered unlikely that mortality would occur between 200 and 300 mg/kg. The anticipated LD50 would therefore be > 300 mg/kg, hence classified in Category 4.

Although not indicated in the report, for classification purposes for use in mixtures a LD50 cut-off value of 500 mg/kgbw is suggested.

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

Quality of whole database:

No study available.
Scientific and exposure related waiving: Corrosive and low likelihood for exposure via inhalation

Acute toxicity: via dermal route

Endpoint conclusion

Quality of whole database:

No study available
Scientific and exposure related waiving: Corrosive and low likelihood for exposure.

Additional information

Acute oral toxicity:

Three groups of Wistar rats, each comprising 2 males and 2 females, received a single oral dose at 25, 200 and 2000 mg/kg body weight of tallow tripropylenetetraamine respectively. The incidence of mortalities for the sexes combined from low to high dose group was 0, 0 and 4. There was no evident sex related effect. All deaths occurred within 1 day of dosing. Signs of toxicity in animals of the high dose group were lethargy and a rough fur. No abnormal clinical behaviour was observed in animals of the 25 mg/kg and 200 mg/kg dose groups and no abnormalities at necropsy. Group mean body weight gain for animals of the low and mid dose groups was normal. Macroscopic examination of animals at necropsy revealed in all animals of the high dose group petechiae of the stomach, a yellow liquid intestinal content and gas accumulation in the intestines. Based on the absence of signs of toxicity in the 200 mg/kg group as well as the absence of abnormalities in this group at necropsy, it is considered unlikely that mortality would occur between 200 and 300 mg/kg. The anticipated LD50 would therefore be > 300 mg/kg, hence classified in Category 4.

 

Comparable other triamines (alkyl dipropylenetriamine) and tetramines (alkyl tripropylenetatraamine) 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 Tetraamines:

           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 tetraamine. 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 cytoplasmatic membrane, leading to lyses of the cell contentand 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 astructurally related branched triamine (Dodecyl dipropylene triamine) for 24 hours, resulted in a dermal penetration of less then 0.01% whereas 0.92% of the applied dose did pass the stratum corneum but remained further fixed in the 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 tripropylenetetraamine 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 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.