Amines, N-C16-18-alkyltrimethylenedi-

Endpoint summary

Description of key information

Low acute toxicity via oral route with LD₅₀cut-off of 2500 mg/kg bw; limited exposure via inhalation; study by dermal route not necessary due to low systemic toxicity and severe dermal irritation.

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:

2007-11-27 to 2007-12-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-guideline 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

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: HsdRccHan: WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen
- Weight at study initiation:
Step 1: 172-180 g
Step 2: 176-177 g

- Fasting period before study: overnight and 3-4 hours after dosing
- Housing: macrolon cages on Altromin saw fibre bedding
- Diet: ad libitum (Altromin 1324 (TPF)
- Water: ad libitum (drinking water)
- Acclimation period: at least 5 days
- Other: marked individually by tail painting, SPF-animals

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

cotton seed oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle:
Step 1: 1.0 g/ 5 mL
2.0 g/ 10 mL
Step 2: 2.0 g/ 10 mL

- Amount of vehicle: 10 mL/ kg body weight
- Justification for choice of vehicle: non-toxic and lipophil
- Lot/batch no. : Lot 067K0116, Sigma Chemicals

MAXIMUM DOSE VOLUME APPLIED: 1.80 mL

DOSAGE PREPARATION : freshly mixed to homogeneity prior to administration

CLASS METHOD
- Rationale for the selection of the starting dose:
the starting dose was choosen to be 2000 mg/kg bw

Doses:

Step 1: 2000 mg/kg bw
Step 2: 2000 mg/kg bw

No. of animals per sex per dose:

Step 1 (2000 mg/kg bw): 3 female rats
Step 2 (2000 mg/kg bw): 3 female rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: A careful clinical examination was made several times on the day of dosing.
Parts of this were at least three observations within the first four hours post-dose.
Animals were observed once a day thereafter.
The animals were weighed prior to the administration and once a week thereafter.

- Necropsy of survivors performed: yes

- Other examinations performed: Cage side observations included changes in the skin and fur, eyes and mucous membranes.
Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity
and behaviour pattern were examined. Particular attention was directed to observations of tremor,
convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Statistics:

not applicable

Sex:

female

Dose descriptor:

approximate LD50

Effect level:

2 500 mg/kg bw

Remarks on result:

other: acute toxic class method; according to GHS (Globally Harmonized Classification System) the test item N-(Hydrogenated tallow)-1,3-diaminopropane was classified into Category 5

Mortality:

Step 1 (2000 mg/kg bw): 28 h post-dose one animal was found dead

Clinical signs:

other: see remarks on results including tables and figures

Gross pathology:

Animal no. 3 of step 1 (2000 mg/ kg bw):
The dead animal was found in a lateral position. Stomach: solid content.
Small and large intestine: partly filled with solid substance.
Animal no.2 of step 2 (2000 mg/ kg bw):
The spleen was enlarged, with a weight of 0.872 g.

Signs of toxicity related to dose level used, time of onset and duration:

Animal no. 1 of step 1 (2000 mg/kg bw): 20 min as well as 125 min post-dose: slightly reduced spontaneous activity, apathy, piloerection. 21 h 05 min as well as 27 h 5 min, 45 h 05 min post-dose: slightly reduced spontaneous activity, piloerection. 51 h 5 min post-dose: slightly reduced spontaneous activity. 69 h 05 min until the end of the observation period: no further symptoms were observed.

Animal no. 2 of step 1 (2000 mg/kg bw): 30 min as well as 3 h post-dose: slightly reduced spontaneous activity, apathy, piloerection. 24 h as well as 45 h post-dose: slightly reduced spontaneous activity, piloerection. 71 h as well as 94 h, 99 h post-dose: piloerection 117 h until the end of the observation period: no further symptoms were observed.

Animal No. 3 of step 1 (2000 mg/kg bw): 30 min post-dose: slightly reduced spontaneous activity, apathy, piloerection. 2 h post-dose: slightly reduced spontaneous activity, apathy, piloerection, salivation. 4 h post-dose: moderately reduced spontaneous activity, apathy, piloerection, salivation. 28 h post-dose: this animal was found dead.

Animal no. 1 of step 2 (2000 mg/kg bw):1 h post-dose: slightly reduced spontaneous activity, apathy, piloerection, stertorousness. 3 h as well as 22 h, 27 h post-dose: piloerection. 45 h until the end of the observation period: no further symptoms were observed.

Animal no. 2 of step 2 (2000 mg/kg bw): 1 h post-dose: slightly reduced spontaneous activity, apathy, piloerection. 3 h as well as 22 h, 27 h, 45 h post-dose: piloerection. 69 h until the end of the observation period: no further symptoms were observed.

Animal no.3 of step 2 (2000 mg/kg bw): 1 h post-dose: piloerection. 4 h as well as 23 h, 28 h, 46 h post-dose: piloerection. 69 h until the end of the observation period: no further symptoms were observed.

Absolute body weights in g :

Animal No.	Sex	Day 0	Day 7	Day 14
Step 1 (2000 mg/kg bw)
1	female	180	195	220
2	female	173	154	193
3	female	172	157-this animal was found dead.
Step 2 (2000 mg/kg bw)
1	female	177	158	195
2	female	177	178	197
3	female	176	184	190

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Considering the reported data of this toxicity test it can be stated that the test item N-(Hydrogenated tallow)-1,3-diaminopropane showed oral toxic
characteristics.
According to GHS (Globally Harmonized Classification System) the test item N-(Hydrogenated tallow)-1,3-diaminopropane was classified into Category 5. (LD50 cut-off: 2500 mg/kg bw).

Executive summary:

The acute oral toxicity test was conducted under GLP according to the guidelines for the acute toxic class method OECD 423, EU method B1.tris and OPPTS 870.110 without deviation.

The acute toxic class method for oral toxicity was performed on nulliparous female HsdRccHan:WIST rats, who received a single exposure of N-(Hydrogenated tallow)-1,3-diaminopropane via oral gavage.

A careful clinical examination was made several times on the day of dosing. Parts of this were at least three observations within the first four hours post-dose. Animals were observed once a day thereafter for 14 days. Cage side observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma. At the end of the observation period the animals were sacrificed by an overdosage of pentobarbital. All animals were subjected to gross necropsy. All gross pathological changes were recorded.

In step 1 three female rat were dosed by oral gavage with 2000 mg N-(Hydrogenated tallow)-1,3-diaminopropane/ kg body weight in cotton seed oil. One of the animals died 28 h post-dose. Signs of slight toxicity indicated by apathy, piloerection and reduced spontaneous activity were observed during the first 3 and 5 days in animal 1 and 2 of step 1, respectively. No further symptoms were observed in these two animals until the end of the observation period. In animal 3 apathy, piloerection, reduced spontaneous activity and salvation were evident after dosing and the animal was found dead 28 h post-dose. In step 2 three additional female rats were dosed with 2000 mg N-(Hydrogenated tallow)-1,3-diaminopropane/ kg body weight. No compound related mortality was recorded for any of these animals. Observed signs of toxicity were reduced spontaneous activity, apathy, pilerection and stertorousness. All animals of step 2 recovered within 3 days. According to the toxic class regime no further testing was required.

Following pathological changes were observed in animal 3 of step 1 (2000 mg/kg bw): The dead animal was found in a lateral position. The stomach as well as small and large intestine were at least partly filled with solid content. Following pathological changes were observed in animal 2 of step 2 (2000 mg/kg bw): The spleen was enlarged, with a weight of 0.872 g.

Considering the reported data of this toxicity test it can be stated that the test item N-(Hydrogenated tallow)-1,3-diaminopropane showed oral toxic characteristics.

According to GHS (Globally Harmonized Classification System) the test item N-(Hydrogenated tallow)-1,3-diaminopropane was classified into Category 5 (LD₅₀cut-off: 2500 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Quality of whole database:

The study is GLP compliant and has Klimisch score 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because skin contact in production and/or use is not likely

the study does not need to be conducted because the physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

The toxic effects following an acute oral dose of N-(hydrogenated tallow alkyl) trimethylenediamine (Amines, N-C16-18-alkyl (evennumbered) propane-1,3-diamine, CAS 133779-11-0, also referred to as HT-diamine) was determined according to the guidelines for the acute toxic class method (OECD 423) performed under GLP.

 

In step 1 three female rats were dosed by oral gavage with 2000 mg N-(hydrogenated tallow alkyl) trimethylenediamine/kg body weight in cotton seed oil. Signs of slight toxicity indicated by apathy, piloerection and reduced spontaneous activity were observed during the first 3 and 5 days in animal 1 and 2 of step 1, respectively. No further symptoms were observed in these two animals until the end of the observation period. In animal 3 apathy, pilo-erection, reduced spontaneous activity and salvation were evident after dosing and the animal was found dead 28 h post-dose. In step 2, three additional female rats were dosed also with 2000 mg/kg body weight. No compound related mortality was recorded for any of these animals. Observed signs of toxicity were reduced spontaneous activity, apathy, pilo-erection and loud breathing. All animals of step 2 recovered within 3 days. According to the toxic class regime no further testing was required.

The LD50 therefore was > 2000 mg/kg bw (LD₅₀cut-off: 2500 mg/kg bw)

 

Inhalation:

There is no study on inhalation toxicity available for N-(hydrogenated tallow alkyl) trimethylenediamine.

REACH stipulates that testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. REACH guidance R.7.a, chapter. 7.4 Acute toxicity, indicates that in principle no inhalation studies are needed when vp < 0.1 Pa at 20°C or particle size > 100 µm. N-(hydrogenated tallow alkyl) trimethylenediamine is a solid (pellets) with no inhalable particles (0.11% (m/m) with particle size < 100 μm) and a vapour pressure less than 0.0015 Pa at 20°C (value based on read-across from shorter chain C_12-14-diamine). Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur, and no acute inhalation test was performed.

 

There is no risk for aspiration as with a mp of 43°C, N-(hydrogenated tallow alkyl) trimethylenediamine is a solid upon ingestion.

 

Dermal:

There is no dermal LD 50 value for acute skin toxicity of N-(hydrogenated tallow alkyl) trimethylenediamine, and due to the severe irritant nature (even eschar formation was observed in all treated animals) of the substance it is not ethical to carry out this animal study. Acute toxicity by oral route resulted to a LD50 cut-off value of 2500 mg/kgbw indicating relative low acute systemic toxicity for which no classification is required. Use and handling of the pure substance is only industrial and professional (formulation), and the classification as irritant of the substance requires risk management methods which eliminate the risk of acute systemic toxicity from potential for skin contact.

Justification for classification or non-classification

No classification for acute toxicity required:

Low systemic toxicity as indicated by Oral LD50 > 2000 mg/kg bw (LD₅₀cut-off: 2500 mg/kg bw).

Dermal systemic toxicity is expected to be very low, while severe irritating properties will limit likelihood of exposures.

Related to low vp and no inhalable particles, there will be no exposures via inhalation.

No classification STOT-SE Cat.3 needed:

The active substance is 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.

N-(hydrogenated tallow alkyl) trimethylenediamine is a solid (pellets) with mp of 43°C, with no inhalable particles (0.11% (m/m) with particle size < 100 μm) and a vapour pressure less than 0.0015 Pa at 20°C (value based on read-across from shorter chain C_12-14-diamine). Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur.