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Description of key information

Available studies result to GHS classification Category 4 for acute oral toxicity (LD50 between 300 and 2000 mg/kg bw) with a LD50 cut-off of 500 mg/kg bw.

No data 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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
July-August 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well reported and carried out study according to guidelines/standards of 1996 instead of 2001 using class 200 mg/kg rather than 300 mg/kg.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
verion of 1996 rather than 2001 used
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: 6 weeks
- Weight at study initiation: 192 ± 5 g (males), 162 ± 10 g (females)
- Fasting period before study: overnight (ca. 18 h) until ca. 4 h after dosing
- Housing: in polycarbonate cages, 3 rats/per sex
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30-70
- Air changes (per hr): ca. 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 23 July To: 19 August 2003
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: not indicated
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no info
- Lot/batch no. (if required): 122K0131
- Purity: not indcated


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


DOSAGE PREPARATION (if unusual): fresh every morning


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: for animal welfare reasons, because no info on toxicity was available, the starting dose was chosen to be 200 mg/kg bw.
Doses:
1. 200 mg/kg (males)
2. 2000 mg/kg (males)
3. 200 mg/kg (females)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: frequently on the day of dosing, at least once a day thereafter; bw weekly
- Necropsy of survivors performed: yes
- Other examinations performed: no
Statistics:
Not required
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Remarks on result:
other: 0/3 females and 1/3 males died at 200 mg/kg, 3/3 males died at 2000 mg/kg
Mortality:
See at clinical signs
Clinical signs:
At the 200 mg/kg dose-level, one male was found dead on day 14; hypoactivity, piloerection and hypersalivation were observed in
this animal on days 1 and 2, but no clinical signs were noted from day 3. In both surviving males, hypoactivity, piloerection and
hypersalivation were recorded on days 1 and 2, and recovery was complete on day 3. In females, no mortality occurred.
Hypoactivity and piloerection, together with dyspnea on day 2, were observed in all animals on days 1 and 2. Then dyspnea,
together with swollen abdomen on days 3 and 4 or noisy breathing between days 12 and 14, was noted in 1/3 females from day 3
to day 5 and from day 12 to day 14. At the 2000 mg/kg, the three males were found dead on day 2; hypoactivity, piloerection and
dyspnea were recorded prior to death.
Body weight:
When compared to historical control animals, a slightly reduced body weight gain was seen in 2/3 females given 200 mg/kg during
the first or second week of the study. The overall body weight gain of both surviving males given 200 mg/kg was not affected by
treatment with the test item.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Other findings:
None
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The oral LD50 of the test item DINORAMOX S3 (batch No. 6751) is comprised between 200 and 2000 mg/kg in male rats. Toxicity is comparable in females. Because only 1 male out of 3 male and 3 female rats dosed at 200 mg/kg died on day 14, it is expected that the LD50 value is higher than 300 mg/kg bw but lower than 2000 mg/kg with LD50 cut-off 500 mg/kg; therefore classification in GHS Category IV is warranted.
Executive summary:

At the request of CECA SA, Paris-la-Défense, France, the acute oral toxicity of the test item DINORAMOX S3 (batch No. 6751) was evaluated in rats according to OECD (No. 423, 22 March 1996) and EC (96/54/EC, B.1 ter, 30 July 1996) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. The test item was prepared in corn oil and was administered by oral route (gavage), at a volume of 10 mL/kg, to groups of fasted Sprague-Dawley rats. The study design was as follows: 3 males 200 mg/kg, 3 males 2000 mg/kg, 3 females 200 mg/kg. Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item. All animals were subjected to necropsy. At the 200 mg/kg dose-level, one male was found dead on day 14; hypoactivity, piloerection and hypersalivation were observed in this animal on days 1 and 2, but no clinical signs were noted from day 3. In both surviving males, hypoactivity, piloerection and hypersalivation were recorded on days 1 and 2, and recovery was complete on day 3. In females, no mortality occurred. Hypoactivity and piloerection, together with dyspnea on day 2, were observed in all animals on days 1 and 2. Then dyspnea, together with swollen abdomen on days 3 and 4 or noisy breathing between days 12 and 14, was noted in 1/3 females from day 3 to day 5 and from day 12 to day 14. At the 2000 mg/kg, the three males were found dead on day 2; hypoactivity, piloerection and dyspnea were recorded prior to death. When compared to historical control animals, a slightly reduced body weight gain was seen in 2/3 females given 200 mg/kg during the first or second week of the study. The overall body weight gain of both surviving males given 200 mg/kg was not affected by treatment with the test item. At necropsy, no apparent abnormalities were observed. Based on these results, the oral LD50 of the test item DINORAMOX S3 (batch No. 6751) is comprised between 200 and 2000 mg/kg in male rats. Toxicity is comparable in females. Because only 1 male out of 3 male and 3 female rats dosed at 200 mg/kg died on day 14, it is expected that the LD50 value is higher than 300 mg/kg bw but lower than 2000 mg/kg, and according to OECD 423 (2001) the LD50 cut-off = 500 mg/kgbw; therefore classification in GHS-OECD Category IV is warranted.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
The study is GLP compliant and has Klimisch score 1

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

Evaluation of the acute toxicity of Tris (2-hydroxyethyl) oleyl diaminopropane (recently redefined as Amines, N-(C18 unsaturated, alkyl) trimethylenedi-, ethoxylated (NLP), CAS 1268344-02-0), also referred to here as Oleyl-diamine3EO:

Oleyl-diamine3EOis similar as other alkyl-diamine3EO substances, severely corrosive. In order to limit animal testing with corrosive material, use is made ofread-across from the tallow-diamine3EO to Oleyl-diamine-3EO. This read-across is acceptable as these chemicals share the same structure and properties. The difference is a slightly lower alkyl chain for the tallow and a higher level of unsaturation of the oleyl. (See also separate document in support to read-across).

 

 

Oral

There are five studies available on alkyl-diamine3EO substances relevant for the evaluation of the acute oral toxicity of Oleyl-diamine3EO. Of these, three studies are not reliable, but these also do not indicate that a more severe classification would be required. 

For evaluation therefore, the following two studies are available:

The first study (selected key-study) evaluated the acute oral toxicity of Tallow-diamine3EO according to the guidelines for the acute toxic class method (OECD 423) performed under GLP.

In step 1 three male rats were dosed by oral gavage with 200 mg Tallow-diamine3EO/kg body weight in corn seed oil. Signs of toxicity observed werehypoactivity, piloerection and hypersalivation on days 1 and 2, and recovery was complete on day 3. However, on day observation day 14, one of the animals was found dead. At the next step 3 males were dosed 2000 mg/kg. All three animals were found dead on day 2. The last step an additional 3 females were also dosed at 200 mg/kg bw. No mortality occurred. All three animals showed hypoactivity and piloerection on days 1 and 2, together with dyspnoea on day 2. Then dyspnoea, together with swollen abdomen on days 3 and 4 or noisy breathing between days 12 and 14, was noted in 1/3 females from day 3 to day 5 and from day 12 to day 14. Body weights of surviving animals were not affected, and at necropsy, no apparent abnormalities were observed. Based on these results, the oral LD50 is between 200 and 2000 mg/kg. Because only 1 male out of 3 male and 3 female rats dosed at 200 mg/kg died on day 14, it is expected that the LD50 value is higher than 300 mg/kg bw but lower than 2000 mg/kg, and according to OECD 423 the LD50 cut-off = 500 mg/kgbw.

 

A second, older study on Tallow-diamine3EO is available, performed according a standard acute method. In this study 5 male rats were dosed0.313, 0.625, 1.25, 2.50 and 5.00 mL/kg bw. Mortality at 1.25 mL/kg bw was 4/5, and at 0.625 mL/kg bw 2/5. At 2.50 and 5.0 mL/kg all animals died within 3 days. At 0.313 mL/kg bw all five animals survived. At gross autopsy all animals dosed at levels above 0.313 mL/kg showed signs of gastric irritation, and upon cut section of the kidneys, congestion of renal tubules. The LD50 was calculated to be 770) mg/kg bw.

 

Overview available data.

Substance

Study

Validity

Results

Tallow-diamine3EO

OECD 423

1

LD50 cut-off 500 mg/kg - key study

Tallow-diamine3EO

OECD 401

2

LD50 770 mg/kg

Tallow-diamine3EO

OECD 401

3

(diluted formulated product) LD50 ca.2400 mg/kg

Tallow-diamine3EO

OECD 401

4

(Abstract - diluted formulated product) LD50 ca.410 mg/kg

Hydrogenated tallow-diamine3EO

OECD 401

4

(identity not indicated in report) LD50 = 860 mg/kg

 

For confirmation of the correct classification of Oleyl-diamine3EO, testing with the substance itself could be considered. However, toxicity results from its corrosive effects and testing with Oleyl-diamine3EO cannot be expected to lead to much different results, and consequently an in vivo acute oral toxicity study with such corrosive substance is not warranted.

 

Inhalation:

There is no study on inhalation toxicity available for Oleyl-diamine3EO.

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.Oleyl-diamine3EOis a (viscous) liquid with a vapour pressure less than 0.0015 Pa at 20°C. 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.

 

Oleyl-diamine3EOis not a pure aliphatic, alicyclic and aromatic hydrocarbons and has a relatively high viscosity (Kinematic viscosity 837 mm2/s at 20 °C) and so do not indicate an immediate concern for aspiration hazard.

 

Dermal:

There is no data available from acute toxicity testing by dermal route for Oleyl-diamine3EO.

Oleyl-diamine3EOis classified for skin corrosion Cat.1B. Due to the severe corrosive nature of the substance it is not ethical to carry out this animal study.

Toxicity following dermal exposure will be characterised by local tissue damage, rather than the result of percutaneously absorbed material. For these severe corrosive substances, the use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. Consequently, the occurrence of substantial dermal exposure of amounts comparable to the levels for acute oral toxicity is unlikely.

Justification for classification or non-classification

Oral LD50 is expected >= 300 mg/kg, and using an LD50 cut-off level of 500 mg/kgbw is appropriate. Oleyl-diamine3EO therefore needs to be classified for acute toxicity according to GHS as Cat.4 with hazard statement H302 “harmful if swallowed”.

 

No data is available regarding acute toxicity by dermal route, but further testing is due to its severe corrosive properties not indicated.

 

Also no acute inhalation studies are available, and in view of lack of exposures no studies are indicated.

 

Oleyl-diamine3EOis not a pure aliphatic, alicyclic and aromatic hydrocarbons and has a relatively high viscosity (Kinematic viscosity 837 mm2/s at 20 °C) and so do not indicate an immediate concern for aspiration hazard.