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Description of key information

Acute oral LD50 > 2000 mg/kg with cut-off > 5000 mg/kg. No dermal LD50 value for di-C16-C18 (evennumbered) alkyl tripropylenetetramine in Wistar rats could be established since the study was terminated before completion of the observation period and number of animals required.

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:
03 July 2015 - 04 August 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(2001)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
(2002)
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:
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 8-9 weeks old)
- Weight at study initiation: 155-164 g (1st group); 159-172 g (2nd group); 153-156 g (3rd group)
- Fasting period before study: Animals were deprived of food overnight prior to dosing
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): set to maintain 18 – 24
- Humidity (%): set to maintain 40 - 70
- Air changes (per hr): set to maintain at least 10
- Photoperiod (hrs dark / hrs light): set to maintain 12/12
Temporary deviations from the maximum and minimum level of daily mean relative humidity occurred. As laboratory historical data do not indicate an effect of the deviations, the study integrity was not adversely affected.

IN-LIFE DATES: From: 03 July 2015 to 04 August 2015
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
(Fagron Capelle a/d IJssel, The Netherlands) (specific gravity 0.92)
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes

Frequency: single dosage, on Day 1

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION
- The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test substance
- Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies
- Adjustment was made for specific gravity of the vehicle
- 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 mortality at the next higher dose
Doses:
- 300 mg/kg bw
- 2000 mg/kg bw
No. of animals per sex per dose:
- 300 mg/kg bw: 3
- 2000 mg/kg bw: 6 (2 groups of three females)
Control animals:
no
Details on study design:
- The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 300 mg/kg bw. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
- Animals were deprived of food until 3-4 hours after administration of the test substance
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occurred.
Mortality:
No mortality occurred.
Clinical signs:
- At 300 mg/kg bw, the animals showed no clinical signs
- At 2000 mg/kg bw, hunched posture and/or piloerection were noted for the animals between Days 1 and 3
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No test substance related abnormalities were found.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an acute oral toxicity study with di-C16-C18 (evennumbered) alkyl tripropylenetetramine in rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw was determined.
Executive summary:

The acute oral toxicity of di-C16-C18 (evennumbered) alkyl tripropylenetetramine was determined in accordance with OECD 423 (2001) and according to GLP principles. Initially, the substance was administered by oral gavage to a group of three female Wistar rats at 300 mg/kg bw. In a stepwise procedure two additional groups of three females were dosed at 2000 mg/kg bw. No mortality occurred. At 300 mg/kg bw, the animals showed no clinical signs. At 2000 mg/kg bw, hunched posture and/or piloerection were noted for the animals between Days 1 and 3. Body weight gain and necropsy did not show any abnormality. The acute oral toxicity (LD50) was determined to be >2000 mg/kg bw. Based on this result, di-C16-C18 (evennumbered) alkyl tripropylenetetramine does not need to be classified for acute toxicity by the oral route according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
According to GLP and guideline

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 19, 2016 - September 26, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
May 2008, including most recent amendments.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147.
Version / remarks:
November 2000, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
dated, 3 November 2015
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
Specific gravity/density: 0.864 at 20°C
No correction was made for the purity/composition of the test item. Adjustment was made for specific gravity of the test item.
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: 192-194 gram.
- Housing: Individually housed in labeled Makrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 18 – 24
- Humidity (%): 40 - 70
- Air changes (per hr): approx 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 19 September 2016 to 26 September 2016
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

The test item was applied on an area of approx. 10% of the total body surface, i.e. approx. 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages.

Frequency: Single dosage, on Day 1.

REMOVAL OF TEST SUBSTANCE
- Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.31 mL/kg bw

Duration of exposure:
24 hours.
Doses:
2000 mg/kg bw (2.31 mL/kg bw)

No. of animals per sex per dose:
3 females/dose
Control animals:
no
Details on study design:
Duration of observation period following administration: 7 days (the study was terminated at day 7 due to severe skin reactions)
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration) and at death.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 7.
- Necropsy : The animals were sacrificed by an oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.
- Other examinations performed: none.
Statistics:
None.
Key result
Sex:
female
Dose descriptor:
LD50
Based on:
test mat.
Remarks on result:
not determinable
Remarks:
Study was terminated before completion of the observation period and number of animals required due to severe skin reactions.
Mortality:
No mortality occured until day 7 when animals were sacrificed for humane reasons.
Clinical signs:
Days 2, 3 and/or 7: Hunched posture, ptosis and piloerection on Days 2, 3 and/or 7
Day 7: Restless behaviour
Body weight:
The changes noted in body weight gain were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
Severe skin reactions were noted for all animals. The skin reactions were visible from removal of the bandage onwards but worsened until day 7 when it was decided to sacrifice the animals for humane reasons and terminated the study.

Day 2: Erythema and grey discoloration of the treated skin
From Day 4 onwards: Thickened areas, scales and/or scabs
From Day 5 onwards: Dry skin
Day 7: Visible wound, animals were scratching the treated skin and were hypersensitive to touch.
Interpretation of results:
study cannot be used for classification
Conclusions:
In an acute dermal toxicity study with rats, performed according to OECD/EC test guidelines and in compliance with GLP principles, no dermal LD50 value for di-C16-C18 (evennumbered) alkyl tripropylenetetramine could be established since the study was terminated before completion of the observation period and number of animals required due to severe skin reactions.
Executive summary:

An acute dermal toxicity study was performed according to OECD/EC guidelines (OECD 402) and in compliance with GLP principles. Di-C16-C18 (evennumbered) alkyl tripropylenetetramine was administered in a step-wise approach to three female Wistar rats by a single dermal application at 2000 mg/kg body weight for 24 hours. Severe skin reactions were noted for all three animals. The skin reactions were visible from removal of the bandage onwards but worsened until day 7 when it was decided to sacrifice the animals for humane reasons and terminate the study. No further animals were treated. Observed clinical signs included hunched posture, ptosis and piloerection on Days 2, 3 and/or 7 and restless behaviour on Day 7. Local skin effects included erythema and grey discoloration on Day 2, thickened areas, scales and/or scabs from Day 4 onwards and dry skin from Day 5 onwards. On Day 7 a wound was visible and animals were hypersensitive to touch and scratching the treated skin. No dermal LD50 value for di-C16-C18 (evennumbered) alkyl tripropylenetetramine in Wistar rats could be established since the study was terminated before completion of the observation period and number of animals required.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
According to GLP and guideline. Not expected to lead to systemic toxicity, however, the severe effects to the skin necessitated premature ending of the study on day 7 for humane reasons.

Additional information

Acute oral toxicity:

di-C16-C18 (evennumbered) alkyl tripropylenetetramine was tested for acute oral toxicity by Acute Toxic Class method (OECD 423). Dosing of 300 mg/kg in 3 female animals did not result in mortality or clinical signs. Six further females were dose 2000 mg/kg. Five animals showed hunched posture on day 1 and done animal between days 1 and 3. No further signs of toxicity were observed.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000

mg/kg body weight. 

 

Acute dermal toxicity:

An acute dermal toxicity study was performed according to OECD/EC guidelines (OECD 402) and in compliance with GLP principles. Di-C16-C18 (evennumbered) alkyl tripropylenetetramine was administered in a step-wise approach to three female Wistar rats by a single dermal application at 2000 mg/kg body weight for 24 hours. Severe skin reactions were noted for all three animals. The skin reactions were visible from removal of the bandage onwards but worsened until day 7 when it was decided to sacrifice the animals for humane reasons and terminate the study. No further animals were treated. Local skin effects included erythema and grey discoloration on Day 2, thickened areas, scales and/or scabs from Day 4 onwards and dry skin from Day 5 onwards. On Day 7 a wound was visible and animals were hypersensitive to touch and scratching the treated skin. No dermal LD50 value for di-C16-C18 (evennumbered) alkyl tripropylenetetramine in Wistar rats could be established since the study was terminated before completion of the observation period and number of animals required.

 

Acute inhalation toxicity:

Physical-chemical properties of di-C16-C18 (evennumbered) alkyl tripropylenetetramine indicate a low likelihood for exposure via inhalation. The viscous liquid has a boiling point > 400 °C and a low vapour pressure (of 1.3 x 10-6 Pa at 20°C). 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. Besides, such testing should normally not be conducted for severely irritating substances.

Justification for classification or non-classification

The cut-off LD50 for oral toxicity in rat has been determined to exceed 2000 mg/kg bw, with a cut-off value higher than 5000 mg/kg bw. The substance therefore need not be classified for acute oral toxicity for GHS.

 

Acute dermal testing could not be cpmpleted due to the irritant effects of the substance, however, 2000 mg.kg bw is not

 

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. Also viscosity and surface tension of di-C16-C18 (evennumbered) alkyl tripropylenetetramine do not give rise for concerns for aspiration.