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Administrative data

Description of key information

Acute oral toxicity: Read-across to long-chain primary alkyl amines of which toxicity is expected to be comparable (with respect to local effects) to higher (with respect to systemic toxicity due to lower absorption) compared to Dimerdiamine. The acute oral LD50 of Hydrogenated tallow > 5000 mg/kg bw. 
A 14-day study for Dimerdiamine at 1000 mg/kg bw/day lead to the mortality of 2/6 animals, and in view of the large difference between acute dose levels and repeated dose levels leading to toxicity, an oral LD50 > 2000 mg/kg bw can also be expected for Dimerdiamine.
There is no information available on acute toxicity via inhalation.
Acute dermal toxicity: Read-across to Coco-alkylamine with an LD50 > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Pemberley Rabbits, Cottenham, Cambridgeshire
- Age at study initiation: 9 to 10 weeks
- Weight at study initiation: 2.0 to 2.2 kg
- Housing: individual housing in metal cages
- Diet (e.g. ad libitum): SDS Standard Rabbit Diet; ad libitum
- Water (e.g. ad libitum): tap water; ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 19
- Humidity (%): 30 - 70
- Air changes (per hr): approx. 19
- Photoperiod (hrs dark / hrs light): 12/12 (19:00-7:00 / 7:00-19:00)
Route of administration:
oral: gavage
Vehicle:
other: methyl cellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50 % (w/v) suspension in 1% methyl cellulose

MAXIMUM DOSE VOLUME APPLIED: 10 mL

Doses:
5000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations daily; weighing on day 1, 8 and 15
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities throughout study
Clinical signs:
other: Pilo-erection, hunched posture, diarrhoea
Gross pathology:
no abnormal findings
Other findings:
no abnormal findings
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Based on the findings of this limit test, the acute median lethal dose (LD 50) of Hydrogenated tallow alkyl amine after a single dose to rats was greater than 5000 mg/kg body weight
Executive summary:

In an GLP compliant OECD TG 401 study, the test material Hydrogenated tallow alkyl amine, a white granular solid (purity 95%), was orally applied to Wistar rats at a dose of 5000 mg/kg bw. The substance was applied as a 50% suspension in 1% methylcellulose (limit-test). There were no deaths, hence, the LD50 exceeded 5000 mg/kg. Clinical signs were diarrhea, piloerection, hunched posture, abnormal gait and pallor of extremities. Complete recovery from these clinical signs was observed by day 5. Body weights were initially reduced but body weight gain was not different from controls by the end of the study (day 15). No treatment-related effects were observed at necropsy. Based on the findings of this study, the acute median lethal dose (LD 50) of Hydrogenated tallow alkyl amine after a single dose to rats was greater than 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Although basically based on cross-reading, the overall weight of evidence leads to a well acceptable conclusion for non-classification of C36-alkylenediamine (Dimerdiamine).

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study similar to Guideline but only 4 animals (2 males/2females) per dose group used
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only 4 animals per dose group used
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CFY
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Interfauna UK Limited, Huntingdon, Cambridgeshire, UK
- Age at study initiation: approx. 6 - 8 weeks
- Weight at study initiation: 200 - 245 g
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
The compound was administered either unchanged at a volume of 0.63 mL/kg (= 500 mg/kg) or in water at a volume of 5 mL/kg (=2000 mg/kg).
Since the compound is described as corrosive and dermal irritative reactions were noted in the 500 mg/kg group (undiluted test material), dilution
for testing of the acute dermal toxicity at 2000 mg/kg bw is justifiable.

TEST SITE
- Area of exposure: 10% of total body surface
- % coverage: 100
- Type of wrap if used: occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.63 ml/kg (undiluted, 500 mg/kg group); 5 ml/kg (40% solution, 2000 mg/kg group)
- Concentration (if solution): 40% in water (only for 2000 mg/kg dose group)

VEHICLE
- water (only for 2000 mg/kg dose group)
Duration of exposure:
24h
Doses:
500 mg/kg bw (undiluted)
2000 mg/kg bw (diluted to 40% w/v in water)
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: daily
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths occured during the study.
Clinical signs:
other: 500 mg/kg/bw: no clinical signs throughout observation period 2000 mg/kg/bw: hunched posture, abnormal gait (waddling), lethargy, and decreased respiratory rate (shortly after treatment, free of symptoms thereafter)
Gross pathology:
Terminal autopsy revealed slight bruising in the subcutaneous tissue of one male and one female rat dosed at 500 mg/kg bw and scab formation with or without ulceration was seen in all rats dosed at 2000 mg/kg bw.
An area of minimal congestion of the stomach (mucosal aspect) was seen in one female rat dosed at 2000 mg/kg bw.
Other findings:
Dermal reactions:
necrosis in all rats dosed at 500 mg/kg bw, persisting until day 12
well defined to moderate oedema in rats dosed at both levels
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute lethal dermal dose (LD 50) of Amine KK to rats was greater than 2000 mg/kg body weight
Executive summary:

In a GLP-compliant study similar to OECD TG 402, the test compound Amine KK (cocoalkylamine), a yellow liquid (purity 100%), was dermally applied under occlusion to Sprague-Dawley rats. At a dose level of 500 mg/kg body weight, the test material was applied undiluted (application volume 0.63 ml/kg bw), at a dose level of 2000 mg/kg bw the substance was diluted to a 40% solution (w/v) in distilled water (application volume 5 ml/kg). Compared to a regular OECD TG 402 study a reduced number of animals were used (4 instead of 5 animals/dose). There were no mortalities; hence, the LD50 is > 2000 mg/kg bw. No clinical signs were observed at 500 mg/kg bw. At 2000 mg/kg, hunched posture, abnormal gait, lethargy and decreased respiratory rate were noted. Signs of dermal reactions at the application site of both treatments were well defined to moderate oedema until days 4-5. Hard scabs, persisting to the end of the observation period, frequently prevented the assessment of oedema.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Although basically based on cross-reading, the overall weight of evidence leads to a well acceptable conclusion for non-classification of C36-alkylenediamine (Dimerdiamine).

Additional information

From the profile information it is clear that the primary alkyl amine and the dimerdiamine structures show a very comparable profile. Both consist of primary amine and large apolar alkyl chain with some level of unsaturation, making it a surface active compound when protonated. Besides aliphatic chains and the primary amines there are no other functional groups. Consequently, the possible type of chemical reaction these substances are capable of will be principally similar. The primary amines groups are positively charged at environmental and physiological conditions (pH ≤ 8).

This cationic surfactant structure has a strong influence on the fate of these substances; they have high adsorptive properties to negatively charged surfaces e.g. particular matter under environmental conditions, and negatively charged cellular membranes. The apolar tails easily dissolve in the membranes, whereas the polar head causes disruption and leakage of the membranes leading to cell damage or lysis of the cell content. As a consequence, the whole molecule will not easily pass membrane structures. Consequently, these substances mainly cause direct effects at the area of contact. In agreement to this, the QSAR Toolbox only indicates mucous membrane irritation by aliphatic amines as a mechanism of toxicity relevant to human health, which specifically refers to reported effects in the stomach upon repeated oral dosing. Also information via dermal exposures shows local effects. Studies on dermal irritation show that Octadecenylamine is corrosive to the skin, and studies on Octadecylamine show maximally irritating response with observations as indurations and desquamation, but no in-depth skin damage indicating corrosion. Also Dimerdiamine has proven to be severely irritating to skin showing to be irreversible within the 14-day observation period.

 

Physico-chemical data show similar tendencies between the dimerdiamine and alkyl amine mixtures as low water solubility, high calculated Pow, low vapour pressure and similar physical state. However, for the dimerdiamine these properties are even more pronounced following which they are expected to be even less bioavailable than the primary fatty amines, and consequently less prone to lead to systemic toxicity..

 

Oral toxicity

For the Dimerdiamine no data from an acute oral study is available.

 

QSARs:

- TOPKAT (Accelrys ADMET Toxicity Prediction (Extensible)) predicts an LD50 of 5.33 g/kgbw. However, it also indicates a very low validity as the substance is out of domain.

- ACD/ToxSuite (ACD Labs ToxSuite v.2.95) also predicts a low acute oral toxicity with LD50 = 3500 mg/kgbw and indicating a moderate reliability.

 

Cross-reading can be done to data obtained from long-chain primary alkyl amines, specifically Octadecenylamine (Oleylamine) on the basis of similarities of structure with same functional groups, properties leading to common biological activity, and common metabolic degradation. For full justification see document “Justification in support of cross-reading from primary fatty amines (PFA) to Dimerdiamine”.

 

Available data: In a GLP compliant OECD TG 401 study, the test material Hydrogenated tallow alkyl amine, a white granular solid (purity 95%), was orally applied to Wistar rats at a dose of 5000 mg/kg bw. The substance was applied as a 50% suspension in 1% methylcellulose (limit-test). There were no deaths; hence, the LD50 exceeded 5000 mg/kg. Clinical signs were diarrhea, piloerection, hunched posture, abnormal gait and pallor of extremities. Complete recovery from these clinical signs was observed by day 5. Body weights were initially reduced but body weight gain was not different from controls by the end of the study (day 15). No treatment-related effects were observed at necropsy. Based on the findings of this study, the acute median lethal dose (LD 50) of Hydrogenated tallow alkyl amine after a single dose to rats was greater than 5000 mg/kg body weight.

 

The combined available data on longer chain primary alkylamines show a general low oral toxicity.

LD50's for longer chain primary alkyl amines (oral) (from EU-RAR for primary alkyl amines, draft 2008):

 1689 mg/kg (Octadecenylamine; CAS No. 112-90-3)

 1900 - > 2000 mg/kg (Tallow-alkylamines; CAS No. 61790-33-8)

 > 2000 mg/kg bw (Octadecylamines; CAS No. 124-30-1)

 > 2000 mg/kg bw (Hydrogenated tallow-alkylamines; CAS No. 61788-45-2)

 

Form this information,Octadecenylamine shows the highest acute toxicity.Dimerdiamine is as much larger molecule expected to show lower absorption and therefore showing lower systemic toxicity.Form comparing repeated dose studies it seems that the dimerdiamine shows much lower toxicity compared to Octadecenylamine. A 28-day study on Octadecenylamine resulted to a NOAEL of 3.25 mg, whereas clear toxic symptoms were seen at 50 mg/kg bw/day. In a 14-day range finding 400 mg/kg bw/day led to mortality and premature sacrifice of the animals.

For Dimerdiamine an OECD 422 study resulted to a NOAEL of 50 mg/kg and only limited toxicity at 500 mg/kg bw/day, and the 14-day range finding study 1000 mg/kg led to the mortality of 2/6 animals.

In view of the large difference between acute dose levels and repeated dose levels leading to toxicity, and the much lower toxicity that dimerdiamine shows in short-term repeated dose studies, an oral LD50 > 2000 mg/kg bw can be expected for Dimerdiamine.

 

Inhalation:

No data available. Due to irritating/corrosive properties respiratory irritation would be in principle possible. Due to the very low vapour pressure (2.2 x10-5 hPa @ 20°C) inhalation of vapours leading to irritation of airways will not occur. Also aerosol exposures are not likely to occur in view of its main use as industrial intermediate under conditions that do not lead to aerosol formation.

No concerns are expected in view of lack of exposure.

 

Normally, aside from concrete evidence in humans, classification/labelling of a substance for aspiration hazard is triggered if it is a hydrocarbon and has a kinematic viscosity of 20.5 mm2/s or less, measured at 40°C. The latter can be obtained as the quotient of dynamic viscosity (in mPa•s) and density (in g/cm3). Estimation can be made for C36-alkylenediamine by calculation with a dynamic viscosity of 316 mPa•s (dynamic) at 20 °C and density of 0.885 g/cm3, resulting to a kinematic viscosity of 357 mm2/s at 20°C. It is not expected that kinematic viscosity will drop below 20.5 mm2/s at 40°C.

 

 

Dermal:

Already all the probably more toxic lower alkyl chain Coco-alkylamine shows an acute LD50 > 2000 mg/kgbw. For comparison, the acute oral LD50 for this substance was found to be LD50: 1300 mg/kg bw (from EU Annex VI report). Dimerdiamine as a twice as big molecule with even lower water solubility and higher calculated Pow compared to Octadecenylamine, and thus also to Coco-alkylamine, can be expected to have certainly a dermal LD50 > 2000 m/kgbw.

Justification for selection of acute toxicity – oral endpoint
Data from cross-reading, leading to sufficient information for decision on classification. Further in vivo testing is not justified.

Justification for selection of acute toxicity – dermal endpoint
Data from cross-reading, leading to sufficient information for decision on classification. Further in vivo testing is not justified.

Justification for classification or non-classification

The evaluation of available data leads to the conclusion that for C36 -alkylenediamine, both the acute oral and acute dermal LD50 can be expected to be above 2000 mg/kg bw, Consequently, C36 -alkylenediamine does not need to be classified for acute oral or dermal toxicity for EU-CLP.

For inhalation route no data is available. However, in view of low likelihood of exposures related to very low vapour pressure no further testing is needed. .

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