1,3-Propanediamine, N-[3-((C11-14, C13-rich)oxy)propyl]- branched acetate

Endpoint summary

Description of key information

The oral LD50 of Etherdiamine C13i/acetate is around 500 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2 February 1990 - 20 February 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Read-across justification
REPORTING FORMAT FOR THE ANALOGUE APPROACH

HYPOTHESIS FOR THE ANALOGUE APPROACH
The substance used for testing is the exact same active chemical Alkyl ether diamine, only without acetic acid being added. Except for the presence of acetic acids, both substances are identical.
The substance for registration is N-[3-(tridecyloxy)propyl]propane-1,3-diamine, branched, which is neutralised with acetic acid, leading to a mixture of 1:1 molar ratio of alkyl etherdiamine and alkyl etherdiamine acetate. As the mw of acetic acid (ca. 60) is much smaller than that of the alkyl etherdiamine (ca. 312), the maximum amount of acetate in the mixture is 9% on mass basis, which means that over 90% is the N-[3-(tridecyloxy)propyl]propane-1,3-diamine, branched itself.
As it is not expected that this relatively small amount of acetic acid significantly contributes to the (systemic) toxicity of N-[3-(tridecyloxy)propyl]propane-1,3-diamine, branched, the studies on the substance without acetic acid can be expected to be fully predictable for the toxicity of the registered product with acetic acid.

SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
No specific information is available. However, it concerns the commercial product, which only differs with respect to the added amount of acetic acid used to nutralise the high pH of the amines.

3. ANALOGUE APPROACH JUSTIFICATION
Gross pathology of deceased animals showed blood stained stomach and intestinal contents, probably caused by the corrosive nature of the test material. Dermal corrosion studies have shown that the presence of acetic acid does not impact the corrosive properties of the compound. Additionally, the conversion of about half of the etherdiamine to etherdiamine-acetate salt, as is the case for the alkyl etherdiamine /acetate product mixture for registration, is not considered to have a large impact as it will probably be dissociated again in stomach and intestinal fluids.

4. DATA MATRIX
Not applicable

Reason / purpose for cross-reference:

read-across source

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: Bantin & Kingman Ltd., England
- Age at study initiation: 5-8 weeks
- Weight at study initiation: males: 120-146g and females 129-140g
- Fasting period before study: overnight
- Housing: animals were housed in groups of up to six by sex in solid-floor polypropylene cages with sawdust bedding.
- Diet (e.g.ad libitum ): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 44-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2 February 1990 To: 20 February 1990

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: depends on dose level between 2.5 and 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual): For the purpose of this study the test material was freshly prepared, as required, at the appropriate concentration as a solution in arachis oil B.P

Doses:

range finding study:
2000, 200 and 25 mg/kg bw

main study:
200 mg/kg bw

No. of animals per sex per dose:

Range finding:
2

Main study:
5

Control animals:

no

Details on study design:

range finding:
- Duration of observation period following administration: 5 days
- Frequency of observations and weighing: on the day of dosing animals were weighed
- Necropsy of survivors performed: no
- Other examinations performed: none

Main study:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Deaths and evidence of overt toxicity were recorded at each observation. Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: none

Statistics:

none

Preliminary study:

In the range finding study all rats died at 2000 mg/kg bw on day 1 and one male animals died on day 4.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 200 - < 2 000 mg/kg bw

Mortality:

In the main study a limit test was performed with doses of 200 mg/kg bw none of the animals died.

Clinical signs:

other: Signs of toxicity were confined to hunched posture and pilo-erection.

Gross pathology:

No abnormalities were noted at necropsy of animals killed at the end of the study.

Other findings:

none

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The acute oral median lethal dose (LD50) o f the test material, LILAFLOT D817, to the Sprague-Dawley strain rat was found to be greater than 200 mg/kg but less than 2000 mg/kg bodyweight. At 200 mg/kg bw 1/14 animals died. LD50 is expected to be > 300 mg/kg: The classification under GHS is Toxicity Category IV.

Executive summary:

A study was performed, according to OECD 401 and under GLP, to determine the acute oral median lethal dose (LD50) of the test material, administered as a solution in arachis oil B.P. in the Sprague-Dawley strain rat . In a range-finding study (2000, 200 and 25 mg/kg bw, 2 animals sex dose) all animals were found dead the next day at 2000 mg/kg bw and one animal died at 200 mg/kg bw at day 4. Following these results a group of ten fasted animals (five males and five females) was given a single oral dose of test material preparation at a dose level of 200 mg/kg bodyweight. There were no deaths. Signs of toxicity were confined to hunched posture and pilo-erection observed 4 hrs after dosing in all animals and on day one in one male. All animals showed expected gain in bodyweight during the study period. No abnormalities were noted at necropsy of animals killed at the end of the study . The acute oral median lethal dose (LD50) o f the test material, LILAFLOT D817, to the Sprague-Dawley strain rat was found to be greater than 200 mg/kg but less than 2000 mg/kg bodyweight. Formal classification under GHS is not possible, but LD50 is expected >= 300 mg/kg, using a LD50 cut-off level of 500 mg/kgbw seems appropriate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Quality of whole database:

Two adequate studies resulting both to a similar LD50 level

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

Acute oral toxicity:

There are two studies available on the etherdiamine product without acetic acid:

The first study involves the evaluation of the acute oral toxicity of etherdiamine C13i in a OECD 401-like study, under GLP. The test material was administered as a solution in arachis oil. In a range-finding study (2000, 200 and 25 mg/kg bw, 2 animals per sex per dose) all animals were found dead the next day at 2000 mg/kg bw and one animal died at 200 mg/kg bw at day 4. In the final study, 10 animals were dosed with 200 mg/kg bw which resulted to no mortality.

The study therefore concluded to a LD50 between 200 and 2000 mg/kg bw. Formal classification under GHS is not possible, but LD50 is expected >= 300 mg/kg, and using a LD50 cut-off level of 500 mg/kgbw seems appropriate.

 

These results are supported by a second available study where acute oral toxicity was evaluated following a OECD 401 study outline. This study resulted to a LD50 of 518 mg/kg bw (c.i.: 442-606 mg/kg) for Etherdiamine C13i. Gross pathology of deceased animals showed blood stained stomach and intestinal contents, probably caused by the corrosive nature of the test material.

 

Both studies indicate a similar level of toxicity for the etherdiamine. Although both studies have been performed on etherdiamine C13i without acetate, they are considered to be relevant for the evaluation of etherdiamine C13i with acetate as well. Dermal corrosion studies have shown that the presence of acetate does not impact the corrosive properties of the compound. Additionally, the conversion of about half of the etherdiamine to etherdiamine-acetate salt, as is the case for theEtherdiamine /acetate product mixture,is not considered to have a large impact as it will probably be dissociated again in stomach and intestinal fluids. The added

 

Acute dermal toxicity:

Etherdiamine C13i/acetate is 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. For 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.

 

Acute inhalation toxicity:

There is no study on inhalation toxicity available on Etherdiamine C13i.

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. Etherdiamine C13i is a liquid with a vapour pressure of 0.005 Pa at 25°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.

Justification for classification or non-classification

LD50 is expected >= 300 mg/kg, and using a LD50 cut-off level of 500 mg/kgbw seems appropriate.

The substance therefore needs to be classified for acute toxicity according to GHS as Cat.4 with hazard statement H302 “harmful if swallowed”.

Acute dermal testing with corrosive materials is not justified. Consequently, 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.

No classification for acute dermal toxicity is therefore indicated.

 

For acute inhalation toxicity the information for classification is lacking, and testing is not justified.

 

Etherdiamine C13i/acetate is not a pure aliphatic, alicyclic and aromatic hydrocarbon and has a relatively high viscosity (Kinematic viscosity 377 mm2/s at 20 °C) and so does not indicate an immediate concern for aspiration hazard.